Chromenone derivatives

ABSTRACT

Novel compounds of the formula I  
                 
 
     in which  
     R 1 , R 2 , R 3  and Het are as defined herein, which  
     are inhibitors of tyrosine kinases and/or Raf kinases and can be employed for the treatment of tumours, for neuroprotection and for protection of the stress proteins of the skin.

BACKGROUND OF THE INVENTION

[0001] The present invention, in one aspect, relates to compounds inwhich the inhibition, regulation and/or modulation of kinase signaltransduction, in particular tyrosine kinase and Raf kinase signaltransduction, plays a role, furthermore to pharmaceutical compositionswhich comprise these compounds, and to the use of the compounds for thetreatment of tyrosine kinase-induced diseases.

[0002] In other aspects, the present invention relates to compoundswhich inhibit, regulate and/or modulate tyrosine kinase signaltransduction, to compositions which comprise these compounds, and tomethods for the use thereof for the treatment of tyrosine kinase-induceddiseases and conditions, such as cancer, tumour growth,arteriosclerosis, age-related macular degeneration, diabeticretinopathy, inflammatory diseases and the like, in mammals.

[0003] Tyrosine kinases are a class of enzymes which catalyse thetransfer of the terminal phosphate of adenosine triphosphate to tyrosineresidues in protein substrates. Tyrosine kinases, through substratephosphorylation, play a crucial role in signal transduction for a numberof cellular functions. Although the precise mechanisms of signaltransduction are still unclear, tyrosine kinases have been shown to beimportant contributing factors in cell proliferation, carcinogenesis andcell differentiation.

[0004] Tyrosine kinases can be categorised as receptor-type tyrosinekinases or non-receptor-type tyrosine kinases. Receptor-type tyrosinekinases have an extracellular portion, a transmembrane portion and anintracellular portion, while non-receptor-type tyrosine kinases areexclusively intracellular.

[0005] Receptor-type tyrosine kinases contain a multiplicity oftransmembrane receptors with different biological activity. Thus, about20 different subfamilies of receptor-type tyrosine kinases have beenidentified. One tyrosine kinase subfamily, known as the HER subfamily,consists of EGFR, HER², HER³ and HER⁴. Ligands from this subfamily ofreceptors include epithelial growth factor, TGF-α, amphiregulin, HB-EGF,betacellulin and heregulin. Another subfamily of these receptor-typetyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IRand IR-R. The PDGF subfamily includes the PDGF-α and -β receptors,CSFIR, c-kit and FLK-II. In addition, there is the FLK family, whichconsists of the kinase insert domain receptor (KDR), foetal liverkinase-1 (FLK-1), foetal liver kinase-4 (FLK-4) and fms tyrosinekinase-1 (flt-1). The PDGF and FLK families are usually discussedtogether due to the similarities between the two groups. For a detaileddiscussion of receptor-type tyrosine kinases, see Plowman et al., DN & P7(6):334-339, 1994, which is hereby incorporated by way of reference.

[0006] Non-receptor-type tyrosine kinases likewise contain amultiplicity of subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70,Fes/Fps, Fak, Jak, Ack and LIMK. Each of these subfamilies is furthersub-divided into different receptors. For example, the Src subfamily isone of the largest subfamilies. It includes Src, Yes, Fyn, Lyn, Lck,Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been linked tooncogenesis. For a more detailed discussion of non-receptor-typetyrosine kinases, see Bolen Oncogene, 8:2025-2031 (1993), which ishereby incorporated by way of reference. Both receptor-type tyrosinekinases and non-receptor-type tyrosine kinases are involved in cellularsignalling pathways leading to numerous pathogenic conditions, includingcancer, psoriasis and hyperimmune responses.

[0007] Various receptor-type tyrosine kinases, and the growth factorsbinding to them, play a role in angiogenesis, although some may promoteangiogenesis indirectly (Mustonen and Alitalo, J. Cell Biol.129:895-898, 1995). One of these receptor-type tyrosine kinases isfoetal liver kinase 1, also referred to as FLK-1. The human analogue ofFLK-1 is the kinase insert domain-containing receptor KDR, which is alsoknown as vascular endothelial cell growth factor receptor 2 or VEGFR-2,since it binds VEGF with high affinity. Finally, the murine version ofthis receptor has also been called NYK (Oelrichs et al., Oncogene8(1):11-15,1993). VEGF and KDR are a ligand-receptor pair which plays avital role in the proliferation of vascular endothelial cells and theformation and sprouting of blood vessels, referred to as vasculogenesisand angiogenesis respectively.

[0008] Angiogenesis is characterised by excessive activity of vascularendothelial growth factor (VEGF). VEGF contains a family of ligands(Klagsburn and D'Amore, Cytokine & Growth Factor Reviews7:259-270,1996). VEGF binds the high affinity membrane-spanning tyrosinekinase receptor KDR and the related fms tyrosine kinase-1, also known asFIt-1 or vascular endothelial cell growth factor receptor 1 (VEGFR-1).Cell culture and gene knockout experiments indicate that each receptorcontributes to different aspects of angiogenesis. KDR mediates themitogenic function of VEGF, whereas Flt-1 appears to modulatenon-mitogenic functions, such as those associated with cellularadhesion. Inhibiting KDR thus modulates the level of mitogenic VEGFactivity. In fact, tumour growth has been shown to be susceptible to theantiangiogenic effects of VEGF receptor antagonists (Kim et al., Nature362, pp. 841-844, 1993).

[0009] Solid tumours can therefore be treated with tyrosine inhibitorssince these tumours depend on angiogenesis for the formation of theblood vessels that are necessary to support their growth. These solidtumours include monocytic leukaemia, carcinomas of the brain, urogenitaltract, lymphatic system, stomach, larynx and lung, including lungadenocarcinoma and small cell lung carcinoma. Further examples includecarcinomas in which overexpression or activation of Raf-activatingoncogenes (for example, K-ras, erb-B) is observed. Such carcinomasinclude pancreatic and breast carcinoma. Inhibitors of these tyrosinekinases are therefore suitable for the prevention and treatment ofproliferative diseases caused by these enzymes.

[0010] The angiogenic activity of VEGF is not limited to tumours. VEGFaccounts for the angiogenic activity produced in or near the retina indiabetic retinopathy. This vascular growth in the retina leads to visualdegeneration culminating in blindness. Ocular VEGF mRNA and proteinlevels are elevated by conditions such as retinal vein occlusion inprimates and decreased pO₂ levels in mice that lead toneovascularisation. Intraocular injections of anti-VEGF monoclonalantibodies or VEGF receptor immunofusions inhibit ocularneovascularisation in both primate and rodent models. Irrespective ofthe cause of induction of VEGF in human diabetic retinopathy, inhibitionof ocular VEGF is suitable for treating this disease.

[0011] Expression of VEGF is also significantly increased in hypoxicregions of animal and human tumours adjacent to areas of necrosis. Inaddition, VEGF is upregulated by the expression of the oncogenes Ras,Raf, Src and mutant p53 (all of which are relevant in combating cancer).Anti-VEGF monoclonal antibodies inhibit the growth of human tumours innude mice. Although the same tumour cells continue to express VEGF inculture, the antibodies do not diminish their mitotic rate. Thus,tumour-derived VEGF does not function as an autocrine mitogenic factor.VEGF therefore contributes to tumour growth in vivo by promotingangiogenesis through its paracrine vascular endothelial cell chemotacticand mitogenic activities. These monoclonal antibodies also inhibit thegrowth of typically less well vascularised human colon carcinomas inathymic mice and decrease the number of tumours arising from inoculatedcells.

[0012] The expression of a VEGF-binding construct of Flk-1, Flt-1, themouse KDR receptor homologue truncated to eliminate the cytoplasmictyrosine kinase domains but retaining a membrane anchor, in virusesvirtually stops the growth of a transplantable glioblastoma in mice,presumably by the dominant negative mechanism of heterodimer formationwith membrane-spanning endothelial cell VEGF receptors.

[0013] Embryonic stem cells, which normally grow as solid tumours innude mice, do not produce detectable tumours if both VEGF alleles areknocked out. Taken together, these data indicate the role of VEGF in thegrowth of solid tumours. Inhibition of KDR or Flt-1 is involved inpathological angiogenesis, and these receptors are suitable for thetreatment of diseases in which angiogenesis is part of the overallpathology, for example inflammation, diabetic retinal vascularisation,as well as various forms of cancer, since tumour growth is known to bedependent on angiogenesis (Weidner et al., N. Engl. J. Med., 324, pp.1-8,1991).

[0014] The present invention furthermore relates to the compounds asinhibitors of Raf kinases.

[0015] Protein phosphorylation is a fundamental process for theregulation of cellular functions. The coordinated action of both proteinkinases and phosphatases controls the degrees of phosphorylation and,hence, the activity of specific target proteins. One of the predominantroles of protein phosphorylation is in signal transduction, whereextracellular signals are amplified and propagated by a cascade ofprotein phosphorylation and dephosphorylation events, for example in thep21^(ras)/Raf pathway.

[0016] The p21^(ras) gene was discovered as an oncogene of the Harvey(H-Ras) and Kirsten (K-Ras) rat sarcoma viruses. In humans,characteristic mutations in the cellular Ras gene (c-Ras) have beenassociated with many different types of cancer. These mutant alleles,which render Ras constitutively active, have been shown to transformcells, such as, for example, the murine cell line NIH 3T3, in culture.

[0017] The p21^(ras) oncogene is a major contributor to the developmentand progression of human solid carcinomas and is mutated in 30% of allhuman carcinomas (Bolton et al. (1994) Ann. Rep. Med. Chem., 29, 165-74;Bos. (1989) Cancer Res., 49, 4682-9). In its normal, unmutated form, theRas protein is a key element of the signal transduction cascade directedby growth factor receptors in almost all tissues (Avruch et al. (1994)Trends Biochem. Sci., 19, 279-83).

[0018] Biochemically, Ras is a guanine nucleotide binding protein, andcycling between a GTP-bound activated and a GDP-bound resting form isstrictly controlled by Ras endogenous GTPase activity and otherregulatory proteins. The Ras gene product binds to guanine triphosphate(GTP) and guanine diphosphate (GDP) and hydrolyses GTP to GDP. Ras isactive in the GTP-bound state. In the Ras mutants in cancer cells, theendogenous GTPase activity is reduced and the protein consequentlytransmits constitutive growth signals to downstream effectors, such as,for example, the enzyme Raf kinase. This leads to the cancerous growthof the cells which carry these mutants (Magnuson et al. (1994) Semin.Cancer Biol., 5, 247-53). The Ras proto-oncogene requires a functionallyintact C-Raf-1 proto-oncogene in order to transduce growth anddifferentiation signals initiated by receptor- and non-receptor-typetyrosine kinases in higher eukaryotes.

[0019] Activated Ras is necessary for the activation of the C-Raf-1proto-oncogene, but the biochemical steps through which Ras activatesthe Raf-1 protein (Ser/Thr) kinase are now well characterised. It hasbeen shown that inhibiting the effect of active Ras by inhibiting theRaf kinase signalling pathway by administration of deactivatingantibodies to Raf kinase or by co-expression of dominant negative Rafkinase or dominant negative MEK (MAPKK), the substrate of Raf kinase,leads to reversion of transformed cells to the normal growth phenotype,see: Daum et al. (1994) Trends Biochem. Sci., 19, 474-80; Fridman et al.(1994) J. Biol. Chem., 269, 30105-8. Kolch et al. (1991) Nature, 349,426-28 and for a review Weinstein-Oppenheimer et al. Pharm. & Therap.(2000), 88, 229-279.

[0020] Similarly, inhibition of Raf kinase (by antisenseoligodeoxynucleotides) has been correlated in vitro and in vivo withinhibition of the growth of a variety of human tumour types (Monia etal., Nat. Med. 1996, 2, 668-75).

[0021] Raf serine- and threonine-specific protein kinases are cytosolicenzymes that stimulate cell growth in a variety of cellular systems(Rapp, U. R., et al. (1988) in The Oncogene Handbook; T. Curran, E. P.Reddy and A. Skalka (eds.) Elsevier Science Publishers; The Netherlands,pp. 213-253; Rapp, U. R., et al. (1988) Cold Spring Harbor Sym. Quant.Biol. 53:173-184; Rapp, U. R., et al. (1990) Inv Curr. Top. Microbiol.Immunol. Potter and Melchers (eds.), Berlin, Springer-Verlag166:129-139).

[0022] Three isozymes have been characterised: C-Raf (Raf-1) (Bonner, T.I., et al. (1986) Nucleic Acids Res. 14:1009-1015). A-Raf (Beck, T. W.,et al. (1987) Nucleic Acids Res. 15:595-609) and B-Raf (Qkawa, S., etal. (1998) Mol. Cell. Biol. 8:2651-2654; Sithanandam, G. et al. (1990)Oncogene:1775). These enzymes differ in their expression in varioustissues. Raf-1 is expressed in all organs and in all cell lines thathave been examined, and A- and B-Raf are expressed in urogenital andbrain tissues respectively (Storm, S. M. (1990) Oncogene 5:345-351).

[0023] Raf genes are proto-oncogenes can initiate malignanttransformation of cells when expressed in specifically altered forms.Genetic changes that lead to oncogenic activation generate aconstitutively active protein kinase by removal of or interference withan N-terminal negative regulatory domain of the protein (Heidecker, G.,et al. (1990) Mol. Cell. Biol. 10:2503-2512; Rapp, U. R., et al. (1987)in Oncogenes and Cancer; S. A. Aaronson, J. Bishop, T. Sugimura, M.Terada, K. Toyoshima and P. K. Vogt (eds.) Japan Scientific Press,Tokyo). Microinjection into NIH 3T3 cells of oncogenically activated,but not wild-type, versions of the Raf protein prepared with Escherichiacoli expression vectors results in morphological transformation andstimulates DNA synthesis (Rapp, U. R., et al. (1987) in Oncogenes andCancer; S. A. Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshimaand P. K. Vogt (ed.) Japan Scientific Press, Tokyo; Smith, M. R., et al.(1990) Mol. Cell. Biol. 10:3828-3833).

[0024] Consequently, activated Raf-1 is an intracellular activator ofcell growth. Raf-1 protein serine kinase is a candidate for thedownstream effector of mitogen signal transduction, since Raf oncogenesovercome growth arrest resulting from a block of cellular Ras activitydue either to a cellular mutation (Ras revertant cells) ormicroinjection of anti-Ras antibodies (Rapp, U. R., et al. (1988) in TheOncogene Handbook, T. Curran, E. P. Reddy and A. Skalka (eds.), ElsevierScience Publishers; The Netherlands, pp. 213-253; Smith, M. R., et al.(1986) Nature (London) 320:540-543).

[0025] C-Raf function plays a role in transformation by a variety ofmembrane-bound oncogenes and for growth stimulation by mitogenscontained in serums (Smith, M. R., et al. (1986) Nature (London)320:540-543). Raf-1 protein serine kinase activity is regulated bymitogens via phosphorylation (Morrison, D. K., et al. (1989) Cell58:648-657), which also effects sub-cellular distribution (Olah, Z., etal. (1991) Exp. Brain Res. 84:403; Rapp, U. R., et al. (1988) ColdSpring Harbor Sym. Quant. Biol. 53:173-184. Raf-1 activating growthfactors include platelet-derived growth factor (PDGF) (Morrison, D. K.,et al. (1988) Proc. Natl. Acad. Sci. USA 85:8855-8859),colony-stimulating factor (Baccarini, M., et al. (1990) EMBO J.9:3649-3657), insulin (Blackshear, P. J., et al. (1990) J. Biol. Chem.265:12115-12118), epidermal growth factor (EGF) (Morrison, R. K., et al.(1988) Proc. Natl. Acad. Sci. USA 85:8855-8859), interleukin-2 (Turner,B. C., et al. (1991) Proc. Natl. Acad. Sci. USA 88:1227) andinterleukin-3 and granulocyte macrophage colony-stimulating factor(Carroll, M. P., et al. (1990) J. Biol. Chem. 265:19812-19817).

[0026] After mitogen treatment of cells, the transiently activated Raf-1protein serine kinase translocates to the perinuclear area and thenucleus (Olah, Z., et al. (1991) Exp. Brain Res. 84:403; Rapp, U. R., etal. (1988) Cold Spring Harbor Sym. Quant. Biol. 53:173-184). Cellscontaining activated Raf are altered in their pattern of gene expression(Heidecker, G., et al. (1989) in Genes and signal transduction inmultistage carcinogenesis, N. Colburn (ed.), Marcel Dekker, Inc., NewYork, pp. 339-374) and Raf oncogenes activate transcription fromAp-I/PEA3-dependent promoters in transient transfection assays (Jamal,S., et al. (1990) Science 344:463466; Kaibuchi, K., et al. (1989) J.Biol. Chem. 264:20855-20858; Wasylyk, C., et al. (1989) Mol. Cell. Biol.9:2247-2250).

[0027] There are at least two independent pathways for Raf-1 activationby extracellular mitogens: one involving protein kinase C (KC) and asecond initiated by protein tyrosine kinases (Blackshear, P. J., et al.(1990) J. Biol. Chem. 265:12131-12134; Kovacina, K. S., et al. (1990) J.Biol. Chem. 265:12115-12118; Morrison, D. K., et al. (1988) Proc. Natl.Acad. Sci. USA 85:8855-8859; Siegel, J. N., et al. (1990) J. Biol. Chem.265:18472-18480; Turner, B. C., et al. (1991) Proc. Natl. Acad. Sci. USA88:1227). In each case, activation involves Raf-1 proteinphosphorylation. Raf-1 phosphorylation may be a consequence of a kinasecascade amplified by autophosphorylation or may be caused entirely byautophosphorylation initiated by binding of a putative activating ligandto the Raf-1 regulatory domain, analogous to PKC activation bydiacylglycerol (Nishizuka, Y. (1986) Science 233:305-312).

[0028] One of the principal mechanisms by which cellular regulation iseffected is through the transduction of extracellular signals across themembrane that in turn modulate biochemical pathways within the cell.Protein phosphorylation represents one course by which intracellularsignals are propagated from molecule to molecule resulting finally in acellular response. These signal transduction cascades are highlyregulated and often overlap, as is evident from the existence of manyprotein kinases as well as phosphatases. Phosphorylation of proteinsoccurs predominantly at serine, threonine or tyrosine residues, andprotein kinases have therefore been classified by their specificity ofphosphorylation site, i.e. serine/threonine kinases and tyrosinekinases. Since phosphorylation is such a ubiquitous process within cellsand since cellular phenotypes are largely influenced by the activity ofthese pathways, it is currently believed that a number of disease statesand/or diseases are attributable to either aberrant activation orfunctional mutations in the molecular components of kinase cascades.Consequently, considerable attention has been devoted to thecharacterisation of these proteins and compounds that are able tomodulate their activity (for a review see: Weinstein-Oppenheimer et al.Pharma. &. Therap., 2000, 88, 229-279).

[0029] The protein kinase PKB (also known as AKT and RAC-PK) is a memberof the AKT/PKB family of serine/threonine kinases and has been shown tobe involved in a diverse set of signalling pathways in human malignancy(Nicholson et al., Cell. Signal., 2002, 14, 381-395). PKB, like othermembers of the AKT/PKB family, is located in the cytosol of unstimulatedcells and translocates to the cell membrane following stimulation. PKBtranslocation can be activated by a number of ligands, includingplatelet-derived growth factor, epidermal growth factor, basicfibroblast growth factor, cellular stress, such as, for example, heatshock and hyperosmolarity, as well as insulin (Bos, Trends Biochem.Sci., 1995, 20, 441-442), and other studies have shown that thisactivation is through PKB kinase which is wortmannin-sensitive (Frankeet al., Science, 1997, 275, 665-668). Once located on the plasmamembrane, PKB has been shown to mediate several functions within thecell, including apoptosis, the metabolic effects of insulin, inductionof differentiation and/or proliferation, protein synthesis and stressresponses (Alessi and Cohen, Curr. Opin. Genet. Dev., 1998, 8, 55-62;Downward, Curr. Opin. Cell Biol., 1998, 10, 262-267).

[0030] PKB was cloned independently in 1991 by three groups (Bellacosaet al., Science, 1991, 254, 274-277; Coffer and Woodgett, Eur. J.Biochem., 1991, 201, 475-481; Jones et al., Cell Regul., 1991, 2,1001-1009), but its association with primary human gastric carcinoma wasrecognised as early as 1987 (Staal et al., Proc. Natl. Acad. Sci. USA,1987, 84, 5034-5037). Sequencing of PKBα revealed homology within thekinase domains to the PKA (about 68%) and PKC isozymes (about 73%)(Jones et al., Proc. Natl. Acad. Sci. U.S.A., 1991, 88, 4171-5), a factthat led to its renaming as PKB. There are three cellular isoforms ofPKB and two splice variants (PKBα, β, β, β₁, β₁; Brazil et al. Trends inBio Sci, 2001, 26, 657-663). PKBα was found to be amplified oroverexpressed in gastric adenocarcinomas and in a breast cancer cellline (Staal et al., Proc. Natl. Acad. Sci. U.S.A., 1987, 84, 5034-7;Jones et al., Cell Regul., 1991, 2, 1001-9). PKBα is amplified oroverexpressed in 3% of breast (Bellacosa et al., Int. J. Cancer, 199564, 280-5), 12% of pancreatic (Cheng et al., Proc. Natl. Acad. Sci.U.S.A., 1996, 93, 3636-41) and 15% of ovarian cancers (Bellacosa et al.,Int. J. Cancer, 1995, 64, 280-5; Cheng et al., Proc. Natl. Acad. Sci.U.S.A., 1992, 89, 9267-71).

[0031] PKBγ is overexpressed in oestrogen receptor-deficient breastcancer and in androgen-independent prostate cell lines (Nakatani et al.,J. Biol. Chem. 1999, 274, 21528-32).

[0032] It has been proposed that PKB is a gene which is involved inchromosomal rearrangement at chromosome band 14q32. This locus is knownto under-go rearrangement in human T-cell malignancies, such as, forexample, prolymphocytic leukaemias and mixed lineage childhoodleukaemias (Staal et al., Genomics, 1988, 2, 96-98).

[0033] PKB also plays a role in the prevention of “programmed celldeath” or apoptosis by inhibitory phosphorylation of ASK-1, Bad,Caspase9 and FKHR (for review see Nicholson et al., Cell Signalling2001, 14, 281-395). It has been shown that PKB provides cells with asurvival signal (for review see Lawlor et al., J. of Cell Science 2001,114, 2903-2910) in order to protect them from a number of agents,including UV radiation (Dudek et al., Science, 1997, 275, 661-665),withdrawal of IGF1 from neuronal cells, detachment from theextracellular matrix, stress and heat shock (Alessi and Cohen, Curr.Opin. Genet. Dev., 1998, 8, 55-62).

[0034] The dual-specific phosphatase PTEN (phosphatase and tensinhomologue deleted on chromosome ten) increases the Ptdlns(3, 4, 5)P₃level in the cell by dephosphorylation of Ptdlns(3, 4, 5)P₃. Ptdlns(3,4, 5)P₃ binds to the PH domain (Pleckstrin homology domain) of PKB. Thisbinding is an essential step for membrane translocation and activationof PKB. PTEN is a tumour suppressor gene mutated in a large proportionof glioblastoma and melanoma cell lines, advanced prostate carcinomasand endometrial carcinomas. Furthermore, it is deleted in >80% ofpatients with hereditary conditions, such as, for example, Cowden'sdisease, Lhermitte-Duclos syndrome and Bannayan-Zonana syndrome. Thepatients display a number of similar features, including multiple benigntumours (harmatomas) and increased susceptibility to breast and thyroidmalignancies (Di Cristofano et al. Cell, 2000, 100, 387-390).

[0035] Cell lines derived from PTEN^(+/−) heterozygous mice (PTEN^(−/−)heterozygous mice are not viable) show increased Ptdlns(3, 4, 5)P₃levels paralleled by increased PKB activity, with concomitant decreasedsensitivity to apoptosis (Di Christofano et al. Nat. Genet. 1998, 19,348-355; Stambolic et al., Cell, 1998, 95, 29-39, Myers et al., Proc.Natl. Acad. Si. U.S.A., 1998, 96 13513-13518).

[0036] PKB is also able to promote cell cycle progression by inhibitingp21 cell cycle inhibitor (Zhou et al.; Nat. Cell Biol., 2002, 3,245-252).

[0037] These findings may explain the overexpression of PKB observed incancer cells which allows preferential survival and proliferation of thecarcinomas by preventing the normal progression to apoptosis.

[0038] At present, there are no known therapeutic agents whicheffectively inhibit the activity of PKB. Consequently, there remains along felt need for agents which are capable of effectively inhibitingPKB function for the activation of pro-apoptotic proteins in all kindsof cancer as chemotherapeutic agents.

[0039] The identification of small compounds which specifically inhibit,regulate and/or modulate signal transduction of tyrosine kinases and/orRaf kinases is therefore desirable and an aim of the present invention.

[0040] It has been found that the compounds of the formula I and saltsand solvates thereof have very valuable pharmacological properties whilebeing well tolerated. In particular, they exhibit tyrosine kinaseinhibiting properties.

[0041] It has furthermore been found that the compounds of the formulaI, and salts and solvates thereof, which are generally described aschromenone derivatives, are inhibitors of the enzyme Raf kinase. Sincethe enzyme is a downstream effector of p21^(ras), the inhibitors proveto be suitable in pharmaceutical compositions for use in human orveterinary medicine where inhibition of the Raf kinase pathway isindicated, for example in the treatment of tumours and/or cancerous cellgrowth mediated by Raf kinase. In particular, the compounds are suitablefor the treatment of human and animal solid cancers, for example murinecancer, since the progression of these cancers is dependent upon the Rasprotein signal transduction cascade and therefore susceptible totreatment by interruption of the cascade, i.e. by inhibiting Raf kinase.Accordingly, the compound of the formula I or a pharmaceuticallyacceptable salt or solvate thereof is administered for the treatment ofdiseases mediated by the Raf kinase pathway, especially cancer,including solid cancers, such as, for example, carcinomas (for exampleof the lungs, pancreas, thyroid, bladder or colon), myeloid diseases(for example myeloid leukaemia) or adenomas (for example villous colonadenoma), pathological angiogenesis and metastatic cell migration. Thecompounds are furthermore suitable for the treatment of complementactivation dependent chronic inflammation (Niculescu et al. (2002)Immunol. Res., 24:191-199) and HIV-1 (human immunodeficiency virustype 1) induced immunodeficiency (Popik et al. (1998) J Virol, 72:6406-6413).

[0042] Surprisingly, it has been found that compounds according to theinvention are able to interact with signalling pathways, especially thesignalling pathways described herein and preferably the Raf kinasesignalling pathway. Chromenone derivatives according to the inventionpreferably exhibit an advantageous biological activity which is easilydemonstrated in enzyme-based assays, for example assays as describedherein. In such enzyme-based assays, chromenone derivatives according tothe invention exhibit an effect, preferably an inhibiting effect, whichis usually documented by IC₅₀ values in a suitable range, preferably inthe micromolar range and more preferably in the nanomolar range.

[0043] As discussed herein, these signalling pathways are relevant forvarious diseases. Accordingly, chromenone derivatives are suitable forthe prophylaxis and/or treatment of diseases that are dependent on thesaid signailing pathways by interacting with one or more of the saidsignalling pathways.

[0044] The present invention therefore in one aspect relates tocompounds according to the invention as promoters or inhibitors,preferably as inhibitors, of the signalling pathways described herein.The invention therefore preferably relates to compounds according to theinvention as promoters or inhibitors, preferably as inhibitors, of theRaf kinase pathway. The invention therefore more preferably relates toderivatives according to the invention as promoters or inhibitors,preferably as inhibitors, of Raf kinase. The invention still morepreferably relates to compounds according to the invention as promotersor inhibitors, preferably as inhibitors, of one or more Raf kinasesselected from the group consisting of A-Raf, B-Raf and C-Raf-1. Theinvention particularly preferably relates to compounds according to theinvention as promoters or inhibitors, preferably as inhibitors, ofC-Raf-1.

[0045] The present invention furthermore relates to the use of one ormore compounds according to the invention in the treatment and/orprophylaxis of diseases, preferably the diseases described herein, thatare caused, mediated and/or propagated by Raf kinases and in particulardiseases that are caused, mediated and/or propagated by Raf kinasesselected from the group consisting of A-Raf, B-Raf and C-Raf-1. Thediseases discussed herein are usually divided into two groups,hyperproliferative and nonhyperproliferative diseases. In thisconnection, psoriasis, arthritis, inflammation, endometriosis, scarring,benign prostatic hyperplasia, immunological diseases, autoimmunediseases and immunodeficiency diseases are to be regarded asnon-cancerous diseases, of which arthritis, inflammation, immunologicaldiseases, autoimmune diseases and immunodeficiency diseases are usuallyregarded as non-hyperproliferative diseases. In this connection, braincancer, lung cancer, squamous cell cancer, bladder cancer, gastriccancer, pancreatic cancer, hepatic cancer, renal cancer, colorectalcancer, breast cancer, head cancer, neck cancer, oesophageal cancer,gynaecological cancer, thyroid cancer, lymphoma, chronic leukaemia andacute leukaemia are to be regarded as cancerous diseases, all of whichare usually regarded as hyperproliferative diseases. Especiallycancerous cell growth and especially cancerous cell growth mediated byRaf kinase is a disease which is a target of the present invention. Thepresent invention therefore relates to compounds according to theinvention as medicaments and/or medicament active ingredients in thetreatment and/or prophylaxis of the said diseases and to the use ofcompounds according to the invention for the preparation of apharmaceutical for the treatment and/or prophylaxis of the said diseasesas well as to a method for the treatment of the said diseases whichcomprises the administration of one or more compounds according to theinvention to a patient in need of such an administration.

[0046] In a comparative measurement, it has furthermore been found thatthe compounds of the formula I act as PKB inhibitors. This action can bedemonstrated, for example, by a method described by Alessi et al. EMBOL. 1996, 15, 6541-6551.

[0047] It can be shown that the compounds according to the inventionhave an antiproliferative action in vivo. The compounds according to theinvention are administered to a patient having a hyperproliferativedisease, for example to inhibit tumour growth, to reduce inflammationassociated with a lymphoproliferative disease, to inhibit transplantrejection or neurological damage due to tissue repair, etc. The presentcompounds are suitable for prophylactic or therapeutic purposes. As usedherein, the term “treatment” is used to refer to both prevention ofdiseases and treatment of pre-existing conditions. The prevention ofproliferation is achieved by administration of the compounds accordingto the invention prior to the development of overt disease, for exampleto prevent the growth of tumours, prevent metastatic growth, diminishrestenosis associated with cardiovascular surgery, etc. Alternatively,the compounds are used for the treatment of on-going diseases bystabilising or improving the clinical symptoms of the patient.

[0048] The host or patient can belong to any mammalian species, forexample a primate species, particularly humans; rodents, including mice,rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal modelsare of interest for experimental investigations, providing a model fortreatment of human disease.

[0049] The susceptibility of a particular cell to treatment with thecompounds according to the invention can be determined by in vitrotests. Typically, a culture of the cell is combined with a compoundaccording to the invention at various concentrations for a period oftime which is sufficient to allow the active agents to induce cell deathor to inhibit migration, usually between about one hour and one week. Invitro testing can be carried out using cultivated cells from a biopsysample. The viable cells remaining after the treatment are then counted.

[0050] The dose varies depending on the specific compound used, thespecific disease, the patient status, etc. A therapeutic dose istypically sufficient considerably to reduce the undesired cellpopulation in the target tissue while the viability of the patient ismaintained. The treatment is generally continued until a considerablereduction has occurred, for example an at least about 50% reduction inthe cell burden, and may be continued until essentially no moreundesired cells are detected in the body.

[0051] For the identification of kinase inhibitors, various assaysystems are available. In scintillation proximity assay (Sorg et al., J.of Biomolecular Screening, 2002, 7, 11-19) and flashplate assay, theradioactive phosphorylation of a protein or peptide as substrate withγATP is measured. In the presence of an inhibitory compound, a decreasedradioactive signal, or none at all, is detectable. Furthermore,homogeneous time-resolved fluorescence resonance energy transfer(HTR-FRET) and fluorescence polarisation (FP) technologies are suitableas assay methods (Sills et al., J. of Biomolecular Screening, 2002,191-214).

[0052] Other non-radioactive ELISA assay methods use specificphospho-antibodies (phospho-ABs). The phospho-AB binds only thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated anti-sheepantibody (Ross et al., 2002, Biochem. J., just about to be published,manuscript BJ20020786).

[0053] There are many diseases associated with deregulation of cellularproliferation and cell death (apoptosis). The conditions of interestinclude, but are not limited to, the following. The compounds accordingto the invention are suitable for the treatment of a number ofconditions where there is proliferation and/or migration of smoothmuscle cells and/or inflammatory cells into the intimal layer of avessel, resulting in restricted blood flow through that vessel, forexample in the case of neointimal occlusive lesions. Occlusive vasculardiseases of interest include atherosclerosis, graft coronary vasculardisease after transplantation,-vein graft stenosis, peri-anastomaticprosthetic restenosis, restenosis after angioplasty or stent placement,and the like.

[0054] The compounds according to the invention are, in addition,suitable as food supplements, for the treatment of diseases and/ordysfunctions which are characterised by oxidative stress conditions andas sunscreens in cosmetic formulations.

PRIOR ART

[0055] WO 92/20642 describes bis-mono- and -bicyclic aryl and heteroarylcompounds which are able to inhibit tyrosine kinase. Chromenonederivatives are not disclosed.

[0056] Chromenone derivatives as constituents of photographic materialsare disclosed in Patent No. JP 07191431 (Application No. JP 0347126).

[0057] Fluorine-containing heteroaryl flavonoids having a fungicidalaction are disclosed in Indian Journal of Chemistry, Section B: OrganicChemistry Including Medicinal Chemistry (1987), 26B(5), 493-5.

[0058] Chromenone derivatives which are described in the literature, butnot in connection with tyrosine kinase inhibition are listed below:

[0059] CAS RN 477545-79-21-[(4-oxo-4H-1-benzopyran-2-yl)carbonyl]-4-phenylpiperazine;

[0060] CAS RN 476298-55-21-[(4-oxo-4H-1-benzopyran-2-yl)carbonyl]-3,5-dimethylpiperidine;

[0061] CAS RN 380469-63-610-[(4-oxo-4H-1-benzopyran-2-yl)carbonyl]phenothiazine;

[0062] CAS RN 380328-67-6 ethyl1-[(4-oxo-4H-1-benzopyran-2-yl)carbonyl]4-piperidinecarboxylate;

[0063] CAS RN 361166-59-81-[(4-oxo-4H-1-benzopyran-2-yl)carbonyl]-1H-indole;

[0064] CAS RN 361166-57-61,2,3,4-tetrahydro-2-[(4-oxo-4H-1-benzopyran-2-yl)carbonyl]isoquinoline;

[0065] CAS RN 361166-50-91,2,3,4-tetrahydro-2-[(4-oxo-4H-1-benzopyran-2-yl)carbonyl]quinoline;

[0066] CAS RN 361166-57-64-[(6-bromo-4-oxo-4H-1-benzopyran-2-yl)carbonyl]morpholine;

[0067] CAS RN 35266741-54-[(6-chloro-4-oxo-4H-1-benzopyran-2-yl)carbonyl]morpholine;

[0068] CAS RN 352667-39-11-[(6-bromo-4-oxo-4H-1-benzopyran-2-yl)carbonyl]pyrrolidine;

[0069] CAS RN 352667-38-01-[(6-bromo-4-oxo-4H-1-benzopyran-2-yl)carbonyl]piperidine; and

[0070] CAS RN 113734-98-82-[(8-bromo-6-fluoro-4-oxo-4H-1-benzopyran-2-yl)carbonyl]thiophene.

SUMMARY OF THE INVENTION

[0071] In one aspect, the invention relates to compounds of the formulaI

[0072] in which

[0073] R¹ is H, —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H,—OSO₃A, —OSO₂A, SO₂A, COOH, COOA, CONH₂, NHSO₂A, COA, CHO or SO₂NH₂,

[0074] R² is H, —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H,—OSO₃A, —OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO orSO₂NH₂,

[0075] R³ is H, —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H,—OSO₃A, —OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO orSO₂NH₂,

[0076] R¹ and R² together are alternatively methylenedioxy orethylenedioxy,

[0077] Het is a monocyclic or bicyclic, saturated, unsaturated oraromatic heterocyclic ring having from 1 to 4 N, O and/or S atoms, whichmay be unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen,═S, ═NH, Hal, A, —(CH₂)_(o)—Ar, —(CH₂)_(o)—cycloalkyl, —(CH₂)_(o)—OH,—(CH₂)_(o)—NH₂, NO₂, CN, —(CH₂)_(o)—COOH, —(CH₂)_(o)—COOA,—(CH₂)_(o)—CONH₂, —(CH₂)_(o)—N HCOA, NHCONH₂, —(CH₂)_(o)—NHSO₂A, CHO,COA′, SO₂NH₂ and/or S(O)_(o)A,

[0078] Ar is phenyl, naphthyl or biphenyl, each of which isunsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NH₂,NO₂, CN, COOH, COOA, CONH₂, NHCOA, NHCONH₂, NHSO₂A, CHO, COA, SO₂NH₂ orS(O)_(o)A,

[0079] A is unbranched or branched alkyl having 1-10 carbon atoms, where1-7H atoms may be replaced by F,

[0080] A′ is alkyl having from 1 to 6 carbon atoms or benzyl,

[0081] Hal is F, Cl, Br or I, and

[0082] o is 0, 1 or 2,

[0083] and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, including mixtures thereof in all ratios.

[0084] The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and to pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, characterised in that

[0085] a) firstly a compound of the formula II

[0086] in which

[0087] R¹ is —OH or —OA,

[0088] R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0089] R³ is H,

[0090] is reacted with a compound of the formula III

[0091] in which A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

[0092] to give a compound of the formula IV

[0093] in which A, R¹, R² and R³ are as defined above,

[0094] b) subsequently the ester IV is reacted with a compound of theformula V

M-Het  V

[0095] in which Het is chromen-2-onyl, benzothiazolyl, thienyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl,imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl,each of which is unsubstituted or mono- or disubstituted by Hal and/orA, and M is sodium, potassium or lithium,

[0096] to give a compound of the formula 1, and/or

[0097] c) a base or acid of the formula I is converted into one of itssalts, or solvates.

[0098] The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.Solvates are, for example, monohydrates or dihydrates or alkoxides.

[0099] The invention also relates to pharmaceutically usable derivativeswhich is taken to mean, for example, the salts of the compoundsaccording to the invention and also so-called prodrug compounds. Theterm prodrug derivatives is taken to mean compounds of the formula Iwhich have been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention. These alsoinclude biodegradable polymer derivatives of the compounds according tothe invention, as described, for example, in Int. J. Pharm. 115, 61-67(1995).

[0100] The invention also relates to mixtures of the compounds of theformula I according to the invention, for example mixtures of twodiastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10,1:100 or 1:1000.

[0101] These are particularly preferably mixtures of stereoisomericcompounds.

[0102] For all radicals which occur more than once, such as, forexample, A, their meanings are independent of one another.

[0103] A is alkyl, is unbranched (linear) or branched and has 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. A is preferably methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl. A is very particularly preferably alkyl having 1, 2, 3,4, 5 or 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl,pentafluoroethyl or 1,1,1-trifluoroethyl.

[0104] A′ is preferably alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl or benzyl.

[0105] OA is alkoxy and is preferably, for example, methoxy, ethoxy,propoxy, isopropoxy, butoxy, trifluoromethoxy or cyclopentoxy.

[0106] —COA (acyl) is preferably acetyl, propionyl, furthermore alsobutyryl, pentanoyl, hexanoyl or, for example, benzoyl.

[0107] Hal is preferably F, Cl or Br, but also I.

[0108] Ar is, for example, unsubstituted phenyl, naphthyl or biphenyl,furthermore preferably phenyl, naphthyl or biphenyl, each of which ismono-, di- or trisubstituted by, for example, A, fluorine, chlorine,bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy,hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl,amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy,sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido,butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxyl,methoxycarbonyl, ethoxycarbonyl or aminocarbonyl. Ar is veryparticularly preferably phenyl.

[0109] Het, apart from the possible substituents, is, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, 4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, furthermore preferably1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or-5-yl, 2,1,3-benzoxadiazol-5-yl or chromenyl. The heterocyclic radicalsmay also be partially or fully hydrogenated. Het can thus also be, forexample, 2,3-dihydro-2-, -3-, 4- or -5-furyl, 2,5-dihydro-2-, -3-, 4- or-5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or-3-thienyl, 2,3-dihydro-1-, -2-, -3-, 4- or -5-pyrrolyl, 2,5-dihydro-1-,-2-, -3-, 4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-,-2- or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, 4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, 4- or -5-yl, hexahydro-1-, -3-or 4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, 4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, 4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylened ioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or -6-yl,2,3-(2-oxo-methylenedioxy)phenyl or 3,4-dihydro-2H-1,5-benzodioxepin-6-or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl or2,3-dihydro-2-oxo-furanyl.

[0110] Het is particularly preferably chromen-2-onyl, benzothiazolyl,thienyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl,isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl orisoquinolyl, each of which is unsubstituted or mono- or disubstituted byHal and/or A.

[0111] R¹ is preferably —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A or—OSO₂A, very particularly preferably —OH or —OA.

[0112] R² is preferably H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A,—OSO₂A or Hal.

[0113] R³ is preferably H.

[0114] R¹ and R² together are preferably alternatively methylenedioxy.

[0115] The compounds of the formula I can occur in variousstereoisomeric forms. The formula I encompasses all these forms.

[0116] Accordingly, the invention relates, in particular, to thecompounds of the formula I in which at least one of the said radicalshas one of the preferred meanings indicated above. Some preferred groupsof compounds can be expressed by the following sub-formulae Ia to Ig,which conform to the formula I and in which the radicals not designatedin greater detail are as defined for the formula 1, but in which

[0117] in Ia R¹ is —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A or —OSO₂A,

[0118] in Ib R¹ is —OH or —OA,

[0119] in Ic R¹ is —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A or —OSO₂A,

[0120] R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0121] R³ is H,

[0122] R¹ and R² together are alternatively methylenedioxy orethylenedioxy,

[0123] in Id R¹ is —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A or —OSO₂A,

[0124] R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0125] R³ is H,

[0126] R¹ and R² together are alternatively methylenedioxy orethylenedioxy,

[0127] Het is a monocyclic or bicyclic, saturated, unsaturated oraromatic heterocyclic ring having from 1 to 4 N, O and/or S atoms, whichmay be unsubstituted or mono-, di- or trisubstituted by Hal and/or A,

[0128] in Ie R¹ is —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A or —OSO₂A,

[0129] R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0130] R³ is H,

[0131] R¹ and R² together are alternatively methylenedioxy orethylenedioxy,

[0132] Het is a monocyclic or bicyclic, aromatic heterocyclic ringhaving from 1 to 3 N, O and/or S atoms, which may be unsubstituted ormono-, di- or trisubstituted by Hal and/or A,

[0133] in If R¹ is —OH or —OA,

[0134] R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0135] R³ is H,

[0136] R¹ and R² together are alternatively methylenedioxy orethylenedioxy,

[0137] Het is chromen-2-onyl, benzothiazolyl, thienyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl,imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl,each of which is unsubstituted or mono- or disubstituted by Hal and/orA,

[0138] A is unbranched or branched alkyl having 1-6 carbon atoms, where1-5H atoms may be replaced by F,

[0139] in Ig R¹ is —OH or —OA,

[0140] R² is H, —OH, —OA or Hal,

[0141] R³ is H,

[0142] R¹ and R² together are alternatively methylenedioxy orethylenedioxy,

[0143] Het is benzothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl or thiazolyl, each ofwhich is unsubstituted or mono- or disubstituted by Hal and/or A,

[0144] A is unbranched or branched alkyl having 1-6 carbon atoms, where1-5H atoms may be replaced by F,

[0145] and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, including mixtures thereof in all ratios.

[0146] The invention relates in particular to the following compounds ofthe formula I:

[0147] 6-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,

[0148] 5,7-dihydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,

[0149] 7-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,

[0150] 6-(1-methyl-1H-imidazole-2-carbonyl)-1,3-dioxolo[4,5g]chromen-8-one,

[0151] 5,7-dihydroxy-2-(pyridine-2-carbonyl)chromen-4-one,

[0152] 6-hydroxy-2-(pyridine-2-carbonyl)chromen-4-one,

[0153] 6-hydroxy-2-(3,5-dichloropyrazine-2-carbonyl)chromen-4-one, and

[0154] 6-hydroxy-2-(benzothiazolyl-2-carbonyl)chromen-4-one,

[0155] and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof are, including mixtures thereof in all ratios.

[0156] The compounds of the formula I and also the starting materialsfor the preparation thereof, in addition, prepared by methods known perse, as described in the literature (for example in the standard works,such as Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

[0157] If desired, the starting materials can also be formed in situ sothat they are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds of the formula I.

[0158] The starting compounds of the formulae II and III are generallyknown. If they are novel, they can, however, be prepared by methodsknown per se.

[0159] Compounds of the formula I can preferably be obtained by firstlyreacting compounds of the formula II with compounds of the formula IIIto give compounds of the formula IV.

[0160] The reaction is carried out by methods which are known to theperson skilled in the art. The reaction is initially carried out in asuitable alcohol in the presence of an alkali or alkaline-earth metalalkoxide, for example in ethanol/sodium ethoxide or methanol/potassiummethoxide.

[0161] In principle, the following inert solvents can also be used.

[0162] Examples of suitable inert solvents are hydrocarbons, such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichloroethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide or dimethylformamide (DMF); nitriles, such asacetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbondisulfide; carboxylic acids, such as formic acid or acetic acid; nitrocompounds, such as nitromethane or nitrobenzene; esters, such as ethylacetate, or mixtures of the said solvents.

[0163] Depending on the conditions used, the reaction time is between afew minutes and 14 days, and the reaction temperature is between about−30° and 140°., normally between −10° and 90°, in particular betweenabout 0° and about 70°.

[0164] The cyclisation to give the compound of the formula IV is carriedout with acid catalysis, by addition of suitable mineral acids, such as,for example, hydrochloric acid, phosphoric acid or sulfuric acid.

[0165] The reaction time and temperature are preferably as indicatedabove.

[0166] The esters of the formula IV are reacted with the compounds ofthe formula V by standard methods in an inert solvent to give thecompounds of the formula I.

[0167] The compound of the formula V employed is preferably Li-Het.

[0168] The inert solvent, reaction time and temperature are preferablyas indicated above, with reaction in THF at from −80 to −75° C. beingparticularly preferred.

[0169] A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in an inert solvent, such as ethanol,followed by evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, or sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids andlaurylsulfuric acid. Salts with physiologically unacceptable acids, forexample picrates, can be used for the isolation and/or purification ofthe compounds of the formula I.

[0170] On the other hand, compounds of the formula I can be convertedinto the corresponding metal salts, in particular alkali metal oralkaline-earth metal salts, or into the corresponding ammonium saltsusing bases (for example sodium hydroxide, potassium hydroxide, sodiumcarbonate or potassium carbonate). It is also possible to usephysiologically acceptable organic bases, such as, for example,ethanolamine.

[0171] Compounds of the formula I according to the invention may bechiral owing to their molecular structure and may accordingly occur invarious enantiomeric forms. They can therefore exist in racemic or inoptically active form.

[0172] Since the pharmaceutical activity of the racemates orstereoisomers of the compounds according to the invention may differ, itmay be desirable to use the enantiomers. In these cases, the end productor even the intermediates can be separated into enantiomeric compoundsby chemical or physical measures known to the person skilled in the artor even employed as such in the synthesis.

[0173] In the case of racemic amines, diastereomers are formed from themixture by reaction with an optically active resolving agent. Examplesof suitable resolving agents are optically active acids, such as the Rand S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaricacid, mandelic acid, malic acid, lactic acid, suitable N-protected aminoacids (for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

[0174] The invention furthermore relates to the use of the compounds ofthe formula I and/or physiologically acceptable salts thereof for thepreparation of a medicament (pharmaceutical preparation), in particularby non-chemical methods. They can be converted here into a suitabledosage form together with at least one solid, liquid and/or semi-liquidexcipient or adjuvant and, if desired, in combination with one or morefurther active ingredients.

[0175] The invention furthermore relates to medicaments comprising atleast one compound of the formula I and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and optionally excipients and/or adjuvants.

[0176] These preparations can be used as medicaments in human orveterinary medicine. Suitable excipients are organic or inorganicsubstances which are suitable for enteral (for example oral), parenteralor topical administration and do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, suchas lactose or starch, magnesium stearate, talc or Vaseline. Suitable fororal administration are, in particular, tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal administration are suppositories, suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, and suitable for topicalapplication are ointments, creams or powders or also as nasal sprays.The novel compounds may also be lyophilised and the resultantlyophilisates used, for example, to prepare injection preparations. Thepreparations indicated may be sterilised and/or comprise adjuvants, suchas lubricants, preservatives, stabilisers and/or wetting agents,emulsifiers, salts for modifying the osmotic pressure, buffersubstances, colorants and flavours and/or a plurality of further activeingredients, for example one or more vitamins.

[0177] The invention furthermore relates to medicaments comprising atleast one compound of the formula I and/or pharmaceutically usablederivatives, solvates, salts and stereoisomers thereof, includingmixtures thereof in all ratios, and at least one further medicamentactive ingredient.

[0178] The invention also relates to a set (kit) consisting of separatepacks of

[0179] (a) an effective amount of a compound of the formula I and/orpharmaceutically usable derivatives, solvates, salts and stereoisomersthereof, including mixtures thereof in all ratios, and

[0180] (b) an effective amount of a further medicament activeingredient.

[0181] The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

[0182] The invention also relates to the use of compounds of thefollowing formula I according to claim 1

[0183] in which

[0184] R¹ is H, —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H,—OSO₃A, —OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO orSO₂NH₂,

[0185] R² is H, —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H,—OSO₃A, —OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO orSO₂NH₂,

[0186] R³ is H, —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H,—OSO₃A, —OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO orSO₂NH₂,

[0187] R¹ and R² together are alternatively methylenedioxy orethylenedioxy,

[0188] Het is a monocyclic or bicyclic, saturated, unsaturated oraromatic heterocyclic ring having from 1 to 4 N, O and/or S atoms, whichmay be unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen,═S, ═NH, Hal, A, —(CH₂)_(o)—Ar, —(CH₂)_(o)—cycloalkyl, —(CH₂)_(o)—OH,—(CH₂)_(o)—NH₂, NO₂, CN, —(CH₂)_(o)—COOH, —(CH₂)_(o)—COOA,—(CH₂)_(o)—CON H₂, —(CH₂)_(o)—N HCOA, N HCON H₂, —(CH₂)_(o)—NHSO₂A, CHO,COA′, SO₂NH₂ and/or S(O)_(o)A,

[0189] Ar is phenyl, naphthyl or biphenyl, each of which isunsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NH₂,NO₂, CN, COOH, COOA, CONH₂, NHCOA, NHCONH₂, NHSO₂A, CHO, COA, SO₂NH₂ orS(O)_(o)A,

[0190] A is unbranched or branched alkyl having 1-10 carbon atoms, where1-7H atoms may be replaced by F,

[0191] A′ is alkyl having from 1 to 6 carbon atoms or benzyl,

[0192] Hal is F, Cl, Br or I,

[0193] o is 0, 1 or 2,

[0194] and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, including mixtures thereof in all ratios,

[0195] for the preparation of a medicament for the treatment of diseasesin which the inhibition, regulation and/or modulation of kinase signaltransduction plays a role.

[0196] Tyrosine kinases and/or Raf kinases are preferred here.

[0197] The invention furthermore relates to the use of compounds of theformula I as described above, and pharmaceutically usable derivatives,solvates, salts and stereoisomers thereof, including mixtures thereof inall ratios, for the preparation of a medicament for the treatment ofdiseases which are influenced by inhibition of tyrosine kinase by thecompounds of the formula I.

[0198] The invention furthermore relates to the use of compounds of theformula I as described above, and pharmaceutically usable derivatives,solvates, salts and stereoisomers thereof, including mixtures thereof inall ratios, for the preparation of a medicament for the treatment ofdiseases which are caused, mediated and/or propagated by Raf kinases,where the Raf kinase is selected from the group consisting of A-Raf,B-Raf and Raf-1.

[0199] The meanings and preferred embodiments generally with respect touses correspond to those mentioned elsewhere in the specification withrespect to the compounds.

[0200] Accordingly, the invention relates in particular to the uses ofthe compounds of the formula I as described above in which at least oneof the radicals mentioned has one of the preferred meanings indicatedabove. Some preferred uses of groups of compounds can be expressed bythe following sub-formulae Ia to Ig, which conform to the formula I andin which the radicals not designated in greater detail are as definedfor the formula I as described above, but in which

[0201] in Ia R¹ is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂Aor Hal;

[0202] in Ib R¹ is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂Aor Hal,

[0203] R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0204] R³ is H,

[0205] R¹ and R² together are alternatively methylenedioxy orethylenedioxy;

[0206] in Ic R¹ is —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0207] R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0208] R³ is H,

[0209] R¹ and R together are alternatively methylenedioxy orethylenedioxy,

[0210] Het is a monocyclic or bicyclic, saturated, unsaturated oraromatic heterocyclic ring having from 1 to 4 N, O and/or S atoms, whichmay be unsubstituted or mono-, di- or trisubstituted by Hal and/or A;

[0211] in Id R¹ is —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A or —OSO₂A,

[0212] R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0213] R³ is H,

[0214] R¹ and R² together are alternatively methylenedioxy orethylenedioxy,

[0215] Het is a monocyclic or bicyclic, saturated, unsaturated oraromatic heterocyclic ring having from 1 to 4 N, O and/or S atoms, whichmay be unsubstituted or mono-, di- or trisubstituted by Hal and/or A;

[0216] in Ie R¹ is —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0217] R² is H, —OH, —OA, phenoxy or —O—CO-A,

[0218] R³ is H,

[0219] R¹ and R together are alternatively methylenedioxy orethylenedioxy,

[0220] Het is a monocyclic or bicyclic, aromatic heterocyclic ringhaving from 1 to 3 N, O and/or S atoms, which may be unsubstituted ormono-, di- or trisubstituted by Hal and/or A;

[0221] in If R¹ is —OH or —OA,

[0222] R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0223] R³ is H,

[0224] R¹ and R² together are alternatively methylenedioxy orethylenedioxy,

[0225] Het is a monocyclic or bicyclic, aromatic heterocyclic ringhaving from 1 to 4 N, O and/or S atoms, which may be unsubstituted ormono-, di- or trisubstituted by Hal and/or A;

[0226] in Ig R¹ is —OH or —OA,

[0227] R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal,

[0228] R³ is H,

[0229] R¹ and R² together are alternatively methylenedioxy orethylenedioxy,

[0230] Het is chromen-2-onyl, benzothiazolyl, thienyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl,imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl,each of which is unsubstituted or mono- or disubstituted by Hal and/orA,

[0231] A is unbranched or branched alkyl having 1-6 carbon atoms, where1-5H atoms may be replaced by F;

[0232] and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, including mixtures thereof in all ratios.

[0233] The present compounds are suitable as pharmaceutical activeingredients for mammals, especially for humans, in the treatment oftyrosine kinase-induced diseases. These diseases include theproliferation of tumour cells, pathological neovascularisation (orangiogenesis) which promotes the growth of solid tumours, ocularneovascularisation (diabetic retinopathy, age-related maculardegeneration and the like) and inflammation (psoriasis, rheumatoidarthritis and the like).

[0234] The present invention encompasses the use of compounds of theformula I and/or physiologically acceptable salts and solvates thereoffor the preparation of a medicament for the treatment or prevention ofcancer. Preferred carcinomas for the treatment originate from the groupconsisting of cerebral carcinoma, urogenital tract carcinoma, carcinomaof the lymphatic system, stomach carcinoma, laryngeal carcinoma and lungcarcinoma. A further group of preferred forms of cancer are monocyticleukaemia, lung adenocarcinoma, small cell lung carcinomas, pancreaticcancer, glioblastomas and breast carcinoma.

[0235] Also encompassed is the use of compounds of the formula I and/orphysiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of a diseasein which angiogenesis is implicated. Such a disease in whichangiogenesis is implicated is an ocular disease, such as retinalvascularisation, diabetic retinopathy, age-related macular degenerationand the like.

[0236] The use of compounds of the formula I and/or physiologicallyacceptable salts and solvates thereof for the preparation of amedicament for the treatment or prevention of inflammatory diseases alsofalls within the scope of the present invention. Examples of suchinflammatory diseases include rheumatoid arthritis, psoriasis, contactdermatitis, delayed hypersensitivity reactions and the like.

[0237] Also encompassed is the use of compounds of the formula I and/orphysiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of atyrosine kinase-induced disease or a tyrosine kinase-induced conditionin a mammal, in which a therapeutically effective amount of a compoundof the formula I is administered to a sick mammal in need of suchtreatment. The therapeutic amount varies according to the specificdisease and can be determined by the person skilled in the art withoutundue effort.

[0238] The present invention also encompasses the use of compounds ofthe formula I and/or physiologically acceptable salts and solvatesthereof for the preparation of a medicament for the treatment orprevention of retinal vascularisation.

[0239] Methods for the treatment or prevention of ocular diseases, suchas diabetic retinopathy and age-related macular degeneration, arelikewise part of the invention. The use for the treatment or preventionof inflammatory diseases, such as rheumatoid arthritis, psoriasis,contact dermatitis and delayed hypersensitivity reactions, as well asthe treatment or prevention of bone pathologies from the groupconsisting of osteosarcoma, osteoarthritis and rickets, likewise fallswithin the scope of the present invention. The term “tyrosinekinase-induced diseases or conditions” refers to pathological conditionsthat depend on the activity of one or more tyrosine kinases. Tyrosinekinases either directly or indirectly participate in the signaltransduction pathways of a variety of cellular activities, includingproliferation, adhesion and migration and differentiation. Diseasesassociated with tyrosine kinase activity include proliferation of tumourcells, pathological neovascularisation that promotes the growth of solidtumours, ocular neovascularisation (diabetic retinopathy, age-relatedmacular degeneration and the like) and inflammation (psoriasis,rheumatoid arthritis and the like).

[0240] The compounds of the formula I or salts or solvents thereof canbe administered to patients for the treatment of cancer. The presentcompounds inhibit tumour angiogenesis, thereby affecting the growth oftumours (J. Rak et al. Cancer Research, 55:4575-4580, 1995). Theangiogenesis-inhibiting properties of the present compounds of theformula I or salts or solvates thereof are also suitable for thetreatment of certain forms of blindness related to retinalneovascularisation.

[0241] The compounds of the formula I or salts or solvates thereof arealso suitable for the treatment of certain bone pathologies, such asosteosarcoma, osteoarthritis and rickets, also known as oncogenicosteomalacia (Hasegawa et al., Skeletal Radiol. 28, pp.4145, 1999;Gerber et al., Nature Medicine, Vol. 5, No. 6, pp.623-628, June 1999).Since VEGF directly promotes osteoclastic bone resorption throughKDR/Flk-1 expressed in mature osteoclasts (FEBS Let. 473:161-164 (2000);Endocrinology, 141:1667 (2000)), the present compounds are also suitablefor the treatment and prevention of conditions related to boneresorption, such as osteoporosis and Paget's disease.

[0242] The compounds can also be used for the reduction or prevention oftissue damage which occurs after cerebral ischaemic events, such asstrokes, by reducing cerebral oedema, tissue damage and reperfusioninjury following ischaemia (Drug News Perspect 11:265-270 (1998); J.Clin. Invest. 104:1613-1620 (1999)).

[0243] The compounds of the formula I or salts or solvates thereof aresuitable for the preparation of a medicament for the treatment ofdiseases which are caused, mediated and/or propagated by Raf kinases,where the Raf kinase is selected from the group consisting of A-Raf,B-Raf and Raf-1. Preference is given to the use for the treatment ofdiseases, preferably from the group consisting of hyperproliferative andnon-hyperproliferative diseases. These are cancerous diseases ornon-cancerous diseases. The non-cancerous diseases are selected from thegroup consisting of psoriasis, arthritis, inflammation, endometriosis,scarring, benign prostatic hyperplasia, immunological diseases,autoimmune diseases and immunodeficiency diseases.

[0244] The cancerous diseases are selected from the group consisting ofbrain cancer, lung cancer, squamous cell cancer, bladder cancer, gastriccancer, pancreatic cancer, hepatic cancer, renal cancer, colorectalcancer, breast cancer, head cancer, neck cancer, oesophageal cancer,gynaecological cancer, thyroid cancer, lymphoma, chronic leukaemia andacute leukaemia.

[0245] The compounds according to the invention can be administered tomammals, preferably humans, either alone or preferably in combinationwith pharmaceutically acceptable excipients or diluents, optionally withknown adjuvants, such as alum, in a pharmaceutical composition,according to standard pharmaceutical practice. The compounds can beadministered orally or parenterally, including the intravenous,intramuscular, intraperitoneal, subcutaneous, rectal and topical routesof administration. On oral use of a chemotherapeutic compound accordingto the invention, the selected compound can be administered, forexample, in the form of tablets or capsules or as an aqueous solution orsuspension. In the case of tablets for oral use, the excipients usuallyused include lactose and corn starch, and lubricants, such as magnesiumstearate, are usually added. On oral administration in capsule form,suitable diluents include lactose and dried corn starch. If aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifiers and suspending agents. If desired, certain sweeteningand/or flavouring agents can be added. On intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be adjusted and buffered in a suitable manner. For intravenoususe, the total concentration of solutes should be set so that thepreparation becomes isotonic. However, the specific dose for theparticular patient depends on a number of factors, for example on theefficacy of the particular compounds used, on the age, body weight,general state of health, sex, on the diet, on the time and method ofadministration, on the excretion rate, the type of administration, themedicament form to be administered, the medicament combination and theseverity of the disease against which the therapy is employed. Theparticular therapeutically effective dose for the particular patient canreadily be determined by routine experiments, for example by the doctoradvising or attending this therapeutic treatment.

[0246] The substances according to the invention are generallypreferably administered in doses of between about 1 and 500 mg, inparticular between 5 and 100 mg per dosage unit. The daily dose ispreferably between about 0.02 and 10 mg/kg of body weight.

[0247] The compounds according to the invention may also be administeredat the same time as other well-known therapeutic agents that areselected for their particular usefulness against the condition that isbeing treated. For example, in the case of bone conditions, combinationsthat would be favourable include those with antiresorptivebisphosphonates, such as alendronate and risedronate; integrin blockers(as defined further below), such as αvβ3 antagonists; conjugatedoestrogens used in hormone replacement therapy, such as Prempro®,Premarin® and Endometrion®; selective oestrogen receptor modulators(SERMs), such as raloxifene, droloxifene, CP-336,156 (Pfizer) andlasofoxifene; cathepsin K inhibitors; and ATP proton pump inhibitors.

[0248] The present compounds are also suitable for combination withknown anti-cancer agents. These known anti-cancer agents include thefollowing: oestrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxic agents, antiproliferativeagents, prenyl-protein transferase inhibitors, HMG-COA reductaseinhibitors, HIV protease inhibitors, reverse transcriptase inhibitorsand other angiogenesis inhibitors. The present compounds areparticularly suitable for administration at the same time asradiotherapy. The synergistic effects of inhibiting VEGF in combinationwith radiotherapy have been described in the art (see WO 00/61186).

[0249] “Oestrogen receptor modulators” refers to compounds whichinterfere with or inhibit the binding of oestrogen to the receptor,regardless of mechanism. Examples of oestrogen receptor modulatorsinclude, but are not limited to, tamoxifen, raloxifene, idoxifene,LY353381, LY 117081, toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646.

[0250] “Androgen receptor modulators” refers to compounds whichinterfere with or inhibit the binding of androgens to the receptor,regardless of mechanism. Examples of androgen receptor modulatorsinclude finasteride and other 5α-reductase inhibitors, nilutamide,flutamide, bicalutamide, liarozole and abiraterone acetate.

[0251] “Retinoid receptor modulators” refers to compounds whichinterfere with or inhibit the binding of retinoids to the receptor,regardless of mechanism. Examples of such retinoid receptor modulatorsinclude bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoicacid, α-difluoromethylornithine, ILX23-7553,trans-N-(4′-hydroxyphenyl)retinamide and N-4-carboxyphenyl retinamide.

[0252] “Cytotoxic agents” refers to compounds which result in cell deathprimarily through direct action on the cellular function or inhibit orinterfere with cell myosis, including alkylating agents, tumour necrosisfactors, intercalators, microtubulin inhibitors and topoisomeraseinhibitors. Examples of cytotoxic agents include, but are not limitedto, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin,lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol,ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide,heptaplatin, estramustine, improsulfan tosylate, trofosfamide,nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin,profiromycin, cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methylpyridine)platinum, benzylguanine,glufosfamide, GPX100,(trans,trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinyl-spermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755 and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyldaunorubicin (see WO00/50032). Examples of microtubulin inhibitors include paclitaxel,vindesine sulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine,docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin,cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258 and BMS188797. Some examples of topoisomerase inhibitors aretopotecan, hycaptamine, irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exobenzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin,BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide,sobuzoxane, 2′-dimethylamino-2′-deoxyetoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5, 10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2-(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]-amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-oneand dimesna. “Antiproliferative agents” include antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 andantimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N′-(3,4-d ichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-mannoheptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b]-1,4-thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamic acid,aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)tetradeca-2,4,6-trien-9-ylaceticacid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N-4-palmitoyl-1-B-D-arabinofuranosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone. “Antiproliferativeagents” also include monoclonal antibodies to growth factors other thanthose listed under “angiogenesis inhibitors”, such as trastuzumab, andtumour suppressor genes, such as p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example).

[0253] The invention furthermore relates to the use of compounds of theformula I and/or physiologically acceptable salts and solvates thereoffor the preparation of a medicament for the treatment of diseases and/ordysfunctions which are characterised by oxidative stress conditions in amammal in need of such treatment, in which a therapeutically effectiveamount of a compound of formula I is administered orally to the mammalin need of such treatment.

[0254] The diseases and/or dysfunctions are, in particular, memory lossand neurodegenerative diseases.

[0255] The compounds according to the invention are therefore used forneuroprotection.

[0256] The use of isoquercetin and ascorbic acid for correspondingpurposes is described in WO 00/54754.

[0257] The invention furthermore relates to the use of the compoundsaccording to the invention and/or physiologically acceptable salts andsolvates thereof as food supplements.

[0258] The invention furthermore relates to a composition comprisingascorbic acid, ascorbate or an ascorbic acid derivative and at least onecompound according to the invention and/or a physiologically acceptablesalt or solvate thereof.

[0259] As flavonoid derivatives, the compounds according to theinvention and salts and solvates thereof have antioxidative properties.

[0260] The use of ectoin derivatives with antioxidants for theprotection of stress proteins of the skin in topical formulations isdescribed, for example, in WO 01/72263.

[0261] The invention therefore relates to the use of the compoundsaccording to the invention and/or physiologically acceptable salts andsolvates thereof in cosmetic formulations, preferably in the form of atopical formulation.

[0262] The invention furthermore relates to the use of the compoundsaccording to the invention and/or physiologically acceptable salts andsolvates thereof for protection of the stress proteins of the skin,preferably in the form of a topical formulation.

[0263] The topical composition is prepared by converting at least one ofthe compounds used in accordance with the invention into a suitableformulation form, if desired with adjuvants and/or excipients. Theadjuvants and excipients originate from the group consisting of thevehicles, preservatives and other conventional adjuvants.

[0264] The topical compositions based on at least one compound used inaccordance with the invention are applied externally to the skin or theskin adnexa.

[0265] Examples of application forms which may be mentioned aresolutions, suspensions, emulsions, pastes, ointments, gels, creams,lotions, powders, soaps, surfactant-containing cleansing preparations,oils and sprays. In addition to one or more compounds used in accordancewith the invention, any desired conventional excipients, adjuvants and,if desired, further active ingredients are added to the composition.

[0266] Preferred adjuvants originate from the group consisting ofpreservatives, antioxidants, stabilisers, solubilisers, vitamins,colorants and odour improvers. Besides one or more compounds used inaccordance with the invention, ointments, pastes, creams and gels maycomprise the conventional excipients, for example animal and vegetablefats, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silica, talc and zincoxide, or mixtures of these substances.

[0267] Besides one or more compounds used in accordance with theinvention, powders and sprays may comprise the conventional excipients,for example lactose, talc, silica, aluminium hydroxide, calcium silicateand polyamide powder, or mixtures of these substances. Sprays mayadditionally comprise the conventional propellants, for examplechlorofluorocarbons, propane/butane or dimethyl ether.

[0268] Besides one or more compounds used in accordance with theinvention, solutions and emulsions may comprise the conventionalexcipients, such as solvents, solubilisers and emulsifiers, for examplewater, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, oils, inparticular cottonseed oils, peanut oil, wheatgerm oil, olive oil, castoroil and sesame oil, glycerol fatty acid esters, polyethylene glycols andfatty acid esters of sorbitan, or mixtures of these substances.

[0269] Besides one or more compounds used in accordance with theinvention, suspensions may comprise the conventional excipients, such asliquid diluents, for example water, ethanol or propylene glycol,suspending agents, for example ethoxylated isostearyl alcohols,polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters,microcrystalline cellulose, aluminium metahydroxide, bentonite,agar-agar and tragacanth, or mixtures of these substances.

[0270] Besides one or more compounds used in accordance with theinvention, soaps may comprise the conventional excipients, such asalkali metal salts of fatty acids, salts of fatty acid monoesters, fattyacid protein hydrolysates, isethionates, lanolin, fatty alcohol,vegetable oils, plant extracts, glycerol, sugars, or mixtures of thesesubstances.

[0271] Besides one or more compounds used in accordance with theinvention, surfactant-containing cleansing products may comprise theconventional excipients, such as salts of fatty alcohol sulfates, fattyalcohol ether sulfates, sulfosuccinic acid monoesters, fatty acidprotein hydrolysates, isethionates, imidazolinium derivatives, methyltaurates, sarcosinates, fatty acid amide ether sulfates,alkylamidobetaines, fatty alcohols, fatty acid glycerides, fatty aciddiethanolamides, vegetable and synthetic oils, lanolin derivatives,ethoxylated glycerol fatty acid esters, or mixtures of these substances.

[0272] Besides one or more compounds used in accordance with theinvention, face and body oils may comprise the conventional excipients,such as synthetic oils, such as fatty acid esters, fatty alcohols,silicone oils, natural oils, such as vegetable oils and oily plantextracts, paraffin oils, lanolin oils, or mixtures of these substances.

[0273] Further typical cosmetic application forms are also lipsticks,lip-care sticks, mascara, eyeliner, eye shadow, rouge, powder make-up,emulsion make-up and wax make-up and sunscreen, pre-sun and after-sunpreparations.

[0274] At least one compound used in accordance with the invention ispresent in the topical composition in an amount of preferably from0.0001 to 50% by weight, particularly preferably from 0.001 to 10% byweight, especially preferably from 0.1 to 1% by weight, based on thecomposition.

[0275] Assays

[0276] The compounds according to the invention described in theexamples were tested by the assays described below and were found tohave kinase inhibitory activity. Other assays are known from theliterature and could readily be performed by the person skilled in theart (see, for example, Dhanabal et al., Cancer Res. 59:189-197; Xin etal., J. Biol. Chem. 274:9116-9121; Sheu et al., Anticancer Res.18:4435-4441; Ausprunk et al., Dev. Biol. 38:237-248; Gimbrone et al.,J. Natl. Cancer Inst. 52:413-427; Nicosia et al., In Vitro 18:538-549).

[0277] VEGF Receptor Kinase Assay

[0278] VEGF receptor kinase activity is measured by incorporation ofradio-labelled phosphate into 4:1 polyglutamic acid/tyrosine substrate(pEY). The phosphorylated pEY product is trapped onto a filter membraneand the incorporation of radiolabelled phosphate is quantified byscintillation counting.

[0279] Materials

[0280] VEGF Receptor Kinase

[0281] The intracellular tyrosine kinase domains of human KDR (Terman,B. I. et al. Oncogene (1991) Vol. 6, pp. 1677-1683.) and Fit-1 (Shibuya,M. et al. Oncogene (1990) Vol. 5, pp. 519-524) were cloned asglutathione S-transferase (GST) gene fusion proteins. This wasaccomplished by cloning the cytoplasmic domain of the KDR kinase as anin frame fusion at the carboxyl terminus of the GST gene. Solublerecombinant GST-kinase domain fusion proteins were expressed inSpodoptera frugiperda (Sf21) insect cells (Invitrogen) using abaculovirus expression vector (pAcG2T, Pharmingen).

[0282] Lysis buffer

[0283] 50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.5% tritonX-100, 10% glycerol, 10 mg/ml each of leupeptin, pepstatin and aprotininand 1 mM phenylmethylsulfonyl fluoride (all Sigma).

[0284] Wash buffer

[0285] 50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% tritonX-100, 10% glycerol, 10 mg/ml each of leupeptin, pepstatin and aprotininand 1 mM phenylmethylsulfonyl fluoride.

[0286] Dialysis buffer

[0287] 50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% tritonX-100, 50% glycerol, 10 mg/ml each of leupeptin, pepstatin and aprotininand 1 mM phenylmethylsulfonyl fluoride.

[0288] 10× reaction buffer

[0289] 200 mM Tris, pH 7.4, 1.0 M NaCl, 50 mM MnCl₂, 10 mM DTT and 5mg/ml bovine serum albumin [BSA] (Sigma).

[0290] Enzyme dilution buffer

[0291] 50 mM Tris, pH 7.4, 0.1 M NaCl, 1 mM DTT, 10% glycerol, 100 mg/mlBSA.

[0292] 10× substrate

[0293] 750 μg/ml poly(glutamic acid/tyrosine; 4:1) (Sigma).

[0294] Stop solution

[0295] 30% trichloroacetic acid, 0.2 M sodium pyrophosphate (bothFisher).

[0296] Wash solution

[0297] 15% trichloroacetic acid, 0.2 M sodium pyrophosphate.

[0298] Filter plates

[0299] Millipore #MAFC NOB, GF/C glass fibre 96 well plate.

[0300] Method A—Protein Purification

[0301] 1. Sf21 cells were infected with recombinant virus at amultiplicity of infection of 5 virus particles/cell and grown at 27° C.for 48 hours.

[0302] 2. All steps were performed at 4° C. Infected cells wereharvested by centrifugation at 1000×g and lysed at 4° C. for 30 minuteswith {fraction (1/10)} volume of lysis buffer followed by centrifugationat 100,000×g for 1 hour. The supernatant was then passed over aglutathione Sepharose column (Pharmacia) equilibrated with lysis bufferand washed with 5 volumes of the same buffer followed by 5 volumes ofwash buffer. Recombinant GST-KDR protein was eluted with wash buffer/10mM reduced glutathione (Sigma) and dialysed against dialysis buffer.

[0303] Method B—VEGF Receptor Kinase Assay

[0304] 1. Add 5 μl of inhibitor or control to the assay in 50% DMSO.

[0305] 2. Add 35 μl of reaction mixture containing 5 μl of 10× reactionbuffer, 5 μl of 25 mM ATP/10 μCi[³³P]ATP (Amersham) and 5 μl of 10×substrate.

[0306] 3. Start the reaction by the addition of 10 μl of KDR (25 nM) inenzyme dilution buffer.

[0307] 4. Mix and incubate at room temperature for 15 minutes.

[0308] 5. Stop the reaction by the addition of 50 μl of stop solution.

[0309] 6. Incubate for 15 minutes at 4° C.

[0310] 7. Transfer a 90 μl aliquot to filter plate.

[0311] 8. Aspirate and wash 3 times with wash solution.

[0312] 9. Add 30 μl of scintillation cocktail, seal plate and count in aWallace Microbeta scintillation counter.

[0313] Human Umbilical Vein Endothelial Cell Mitogenesis Assay

[0314] Expression of VEGF receptors that mediate mitogenic responses tothe growth factor is largely restricted to vascular endothelial cells.Human umbilical vein endothelial cells (HUVECs) in culture proliferatein response to VEGF treatment and can be used as an assay system toquantify the effects of KDR kinase inhibitors on VEGF stimulation. Inthe assay described, quiescent HUVEC monolayers are treated with vehicleor test compound 2 hours prior to addition of VEGF or basic fibroblastgrowth factor (bFGF). The mitogenic response to VEGF or bFGF isdetermined by measuring the incorporation of [³H]thymidine into cellularDNA.

[0315] Materials

[0316] HUVECs

[0317] HUVECs frozen as primary culture isolates are obtained fromClonetics Corp. Cells are maintained in endothelial growth medium (EGM;Clonetics) and are used for mitogenic assays at passages 3-7.

[0318] Culture Plates

[0319] NUNCLON 96-well polystyrene tissue culture plates (NUNC #167008).

[0320] Assay Medium

[0321] Dulbecco's modification of Eagle's medium containing 1 g/mlglucose (low-glucose DMEM; Mediatech) plus 10% (v/v) foetal bovine serum(Clonetics).

[0322] Test Compounds

[0323] Working stock solutions of test compounds are diluted serially in100% dimethyl sulfoxide (DMSO) to 400 times greater than their desiredfinal concentrations. Final dilutions to 1× concentration are made intoassay medium immediately prior to addition to cells.

[0324] 10× growth factors

[0325] Solutions of human VEGF 165 (500 ng/ml; R&D Systems) and bFGF (10ng/ml; R&D Systems) are prepared in assay medium.

[0326] 10×[³H]thymidine

[0327] [Methyl-3H]thymidine (20 Ci/mmol; Dupont-NEN) is diluted to 80μCi/ml in low-glucose DMEM.

[0328] Cell Wash Medium

[0329] Hank's balanced salt solution (Mediatech) containing 1 mg/mlbovine serum albumin (Boehringer-Mannheim).

[0330] Cell Lysis Solution

[0331] 1 N NaOH, 2% (w/v) Na₂CO₃.

[0332] Method 1

[0333] HUVEC monolayers maintained in EGM are harvested bytrypsinisation and plated out at a density of 4000 cells per 100 μl ofassay medium per well in 96-well plates. Cell growth is arrested for 24hours at 37° C. in a humidified atmosphere containing 5% CO₂.

[0334] Method 2

[0335] Growth-arrest medium is replaced by 100 μl of assay mediumcontaining either vehicle (0.25% [v/v] DMSO) or the desired finalconcentration of test compound. All determinations are performed intriplicate. Cells are then incubated at 37° C./5% CO₂ for 2 hours toallow test compounds to enter cells.

[0336] Method 3

[0337] After the 2-hour pre-treatment period, cells are stimulated byaddition of 10 μl/well of either assay medium, 10×VEGF solution or10×bFGF solution. Cells are then incubated at 37° C./5% CO₂.

[0338] Method 4

[0339] After 24 hours in the presence of growth factors, 10×[³H]thymidine (10 μl/well) is added.

[0340] Method 5

[0341] Three days after addition of [³H]thymidine, medium is removed byaspiration, and cells are washed twice with cell wash medium (400μl/well followed by 200 μl/well). The washed, adherent cells are thensolubilised by addition of cell lysis solution (100 μl/well) and warmingto 37° C. for 30 minutes. Cell lysates are transferred to 7 ml glassscintillation vials containing 150 μl of water. Scintillation cocktail(5 ml/vial) is added, and cell-associated radioactivity is determined byliquid scintillation spectroscopy. According to these assays, thecompounds of the formula I are inhibitors of VEGF and are thus suitablefor the inhibition of angiogenesis, such as in the treatment of oculardiseases, for example diabetic retinopathy, and for the treatment ofcarcinomas, for example solid tumours. The present compounds inhibitVEGF-stimulated mitogenesis of human vascular endothelial cells inculture with IC50 values of 0.01-5.0 μM. These compounds also showselectivity over related tyrosine kinases (for example FGFR¹ and the Srcfamily; for relationship between Src kinases and VEGFR kinases, seeEliceiri et al., Molecular Cell, Vol. 4, pp.915-924, December 1999).

[0342] Test for Investigating the Free-Radical Scavenger Properties orAntioxidative Action

[0343] The assay serves for screening the antioxidative or free-radicalscavenger property of a substance or extract. In order to determine thisproperty, the substance is allowed to react with the stable free radicalDPPH* (2,2-diphenyl-1-picrylhydrazyl hydrate) in ethanol solution. Thereduction of DPPH* is followed via the drop in absorbance at thecharacteristic wavelength of the free radical. In its free-radical form,DPPH* absorbs at 515 nm, while on reduction by an antioxidant (AOX), theabsorbance drops. Different concentrations are investigated for eachantioxidant (expressed as the ratio of mol of antioxidant/mol of DPPH*).The drop in absorbance at 515 nm is determined after 1 second, 2minutes, 10 minutes and then every 10 minutes until the absorbanceremains constant. The precise initial concentration of DPPH* isdetermined with the aid of the absorption coefficient. At eachantioxidant concentration, the remaining DPPH* concentration isdetermined as percent of the starting concentration and plotted againstthe molar ratio of antioxidant with DPPH*. The anti-free-radicalactivity is defined as the proportion of antioxidant which lowers theDPPH concentration to 50 percent of the initial amount (efficientconcentration=EC₅₀). The smaller this value, the greater the activityagainst free radicals. The reaction behaviour of the individualantioxidants varies greatly. A distinction can be drawn between fast-,medium- and slow-reacting substances, with the steady state beingreached between 30 seconds and 12 hours.

[0344] Above and below, all temperatures are indicated in ° C. and, allparts and percentages are by weight, unless otherwise indicated. In thefollowing examples, “conventional work-up” means that, if necessary,water is added, the pH is adjusted, if necessary, to a value of between2 and 10, depending on the constitution of the end product, the mixtureis extracted with ethyl acetate or dichloromethane, the phases areseparated, the organic phase is dried over sodium sulfate andevaporated, and the product is purified by chromatography on silica geland/or by crystallisation. Rf values on silica gel; eluent: ethylacetate/methanol 9:1.

[0345] Mass spectrometry (MS): El (electron impact ionisation) M⁺

[0346] FAB (fast atom bombardment) (M+H)⁺

[0347] ESI (electrospray ionisation) (M+H)⁺ (unless stated otherwise).

[0348] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The preceding preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

EXAMPLE 1

[0349] Preparation of6-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one

[0350] 1.1 3.8 g of sodium are dissolved in portions in 300 ml ofethanol with stirring. A solution of 5.0 g of 2,5-dihydroxyacetophenoneand 17.8 ml of diethyl oxalate in 25 ml of ethanol is subsequently addeddropwise. The reaction mixture is then heated at 800 for 3 hours andcooled to room temperature, and 10 ml of 32% HCl are added dropwise. Themixture is heated at 90° for 30 minutes and cooled, and the solvent isremoved. Conventional work-up gives 5.6 g of6-hydroxy-2-ethoxycarbonylchromen-4-one (“AA”).

[0351] 1.2 2.4 ml of 1.6 M n-BuLi solution are added to a solution,cooled to −78°, of 0.3 ml of 1-methyl-1H-imidazole in 5 ml of THF underan N₂ atmosphere, and the mixture is stirred for a further 30 minutes. Asolution of 300 mg of “AA” in 5 ml of THF is subsequently added, and themixture is stirred for a further 1 hour. Conventional work-up gives 303mg of 6-hydroxy-2-(1-methyl-1 H-imidazole-2-carbonyl)chromen-4-one.

[0352]¹H NMR (DMSO-d₆) 64.02 (s, 3H), 7.32 (m, 3H), 7.59 (s, 1H), 7.62(dd, J=9.6, 2.0 Hz, 1H), 7.74 (s, 1H), 10.21(s, 1H).

[0353]¹³C NMR (DMSO-d₆) δ 36.1, 107.2, 115.3, 120.3, 124.2, 124.6,129.7, 129.9, 141.1, 149.2, 155.2, 156.0, 174.8, 177.4.

[0354] El MS (m/e) 267 (M+), 239, 211

[0355] UV-Vis (^(i)PrOH): λ_(max). (Ig. ε):

[0356] The following compounds are obtained analogously:

[0357] 6-hydroxy-2-(1-methyl-1H-imidazolee-2-carbonyl)chromen-4-one,

[0358] 5,7-dihydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,

[0359] 7-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,

[0360] 6-(11-methyl-1H-imidazole-2-carbonyl)-1,3-dioxolo[4,5g]chromen-8-one,

[0361] 5,7-dihydroxy-2-(pyridine-2-carbonyl)chromen-4-one,

[0362] 6-hydroxy-2-(pyridine-2-carbonyl)chromen-4-one,

[0363] 6-hydroxy-2-(3,5-dichloropyrazine-2-carbonyl)chromen-4-one,

[0364] 6-hydroxy-2-(benzothiazolyl-2-carbonyl)chromen-4-one.Pharmacological test results Inhibition of PKB IC₅₀ (μmol) Inhibition ofRAF IC₅₀ (μmol) Inhibition of Tie2 IC₅₀ (μmol)

9.4 >1.0 >10

>10 >1.0 >10

>10 >1.0 >10

>10 >1.0 >10

>10 >1.0 >10

>10 >1.0 >10

[0365] The following examples relate to pharmaceutical preparations:

EXAMPLE A Injection Vials

[0366] A solution of 100 g of an active ingredient of the formula I and5 g of disodium hydrogenphosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised under sterile conditionsand sealed under sterile conditions. Each injection vial contains 5 mgof active ingredient.

EXAMPLE B Suppositories

[0367] A mixture of 20 g of an active ingredient of the formula I with100 g of soya lecithin and 1400 g of cocoa butter is melted, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

[0368] A solution is prepared from 1 g of an active ingredient of theformula I, 9.38 g of NaH₂PO₄ 2H₂O, 28.48 g of Na₂HPO₄ 12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

[0369] 500 mg of an active ingredient of the formula I are mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE E Tablets

[0370] A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed to give tablets in a conventional manner in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

[0371] Tablets are pressed analogously to Example E and subsequentlycoated in a conventional manner with a coating of sucrose, potatostarch, talc, tragacanth and dye.

EXAMPLE G Capsules

[0372] 2 kg of active ingredient of the formula I are introduced intohard gelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

[0373] A solution of 1 kg of active ingredient of the formula I in 60 lof bidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

[0374] The entire disclosures of all applications, patents andpublications, cited herein and of corresponding German application No.10319552.1, filed Apr. 30, 2003, and German application No. 10335782.3filed Aug. 5, 2003 are incorporated by reference herein.

[0375] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0376] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A method of treating a disease in which the inhibition, regulationand/or modulation of kinase signal transduction plays a role, comprisingadministering to a patient in need thereof an effective amount of acompound, salt, or solvate of formula I, or a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and said compound, saltor solvate of formula I

in which R¹ is H, —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H,—OSO₃A, —OSO₂A, SO₂A, COOH, COOA, CONH₂, NHSO₂A, COA, CHO or SO₂NH₂, R²is H, —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H, —OSO₃A,—OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO or SO₂NH₂, R³ isH, —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H, —OSO₃A, —OSO₂A,SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO or SO₂NH₂, R¹ and R²together are alternatively methylenedioxy or ethylenedioxy, Het is amonocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclicring having from 1 to 4 N, O and/or S atoms, which may be unsubstitutedor mono-, di- or trisubstituted by carbonyl oxygen, ═S, ═NH, Hal, A,—(CH₂)_(o)—Ar, —(CH₂)_(o)—Cycloalkyl, —(CH₂)_(o)—OH, —(CH₂)_(o)—NH₂,NO₂, CN, —(CH₂)_(o)—COOH, —(CH₂)_(o)—COOA, —(CH₂)_(o)—CONH₂,—(CH₂)_(o)—NHCOA, NHCONH₂, —(CH₂)_(o)—NHSO₂A, CHO, COA′, SO₂NH₂ and/orS(O)OA, Ar is phenyl, naphthyl or biphenyl, each of which isunsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NH₂,NO₂, CN, COOH, COOA, CONH₂, NHCOA, NHCONH₂, NHSO₂A, CHO, COA, SO₂NH₂ orS(O)_(o)A, A is unbranched or branched alkyl having 1-10 carbon atoms,where 1-7H atoms may be replaced by F, A′ is alkyl having from 1 to 6carbon atoms or benzyl, Hal is F, Cl, Br or I, and o is 0, 1 or
 2. 2. Amethod according to claim 1, wherein the kinase whose transduction isaffected is a tyrosine kinase or Raf kinase.
 3. A method according toclaim 1, wherein a tyrosine kinase is inhibited.
 4. A method accordingto claim 3, wherein the disease treated is a solid tumour.
 5. A methodaccording to claim 4, wherein the solid tumour is brain tumour, tumourof the urogenital tract, tumour of the lymphatic system, stomach tumour,laryngeal tumour or lung tumour.
 6. A method according to claim 4,wherein the solid tumour is monocytic leukaemia, lung adenocarcinoma,small cell lung carcinoma, pancreatic cancer, glioblastoma or breastcarcinoma.
 7. A method according to claim 3, wherein the disease treatedis affected by angiogenesis.
 8. A method according to claim 7, whereinthe disease treated is an ocular disease.
 9. A method according to claim3, wherein the disease treated is retinal vascularisation, diabeticretinopathy, age-related macular degeneration or an inflammatorydisease.
 10. A method according to claim 9, wherein the inflammatorydisease is rheumatoid arthritis, psoriasis, contact dermatitis ordelayed hypersensitivity reaction.
 11. A method according to claim 3,wherein the disease treated is osteoarthritis or rickets.
 12. A methodaccording to claim 3, further comprising administering 1) an oestrogenreceptor modulator, 2) an androgen receptor modulator, 3) a retinoidreceptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent,6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductaseinhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptaseinhibitor or 10) an angiogenesis inhibitor.
 13. A method according toclaim 3, further comprising administering radiotherapy.
 14. A methodaccording to claim 1, wherein the disease is treated, mediated and/orpropagated by Raf kinase.
 15. A method according to claim 14, whereinthe Raf kinase is A-Raf, B-Raf or Raf-1.
 16. A method according to claim14, wherein the disease treated is a hyperproliferative disease.
 17. Amethod according to claim 14, wherein the disease treated is cancerous.18. A method according to claim 14, wherein the disease treated isnoncancerous.
 19. A method according to claim 14, wherein thenon-cancerous disease is psoriasis, arthritis, inflammation,endometriosis, scarring, benign prostatic hyperplasia, an immunologicaldisease, an autoimmune disease or an immunodeficiency disease.
 20. Amethod according to claim 14, wherein the disease is brain cancer, lungcancer, squamous cell cancer, bladder cancer, gastric cancer, pancreaticcancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer,head cancer, neck cancer, oesophageal cancer, gynaecological cancer,thyroid cancer, lymphoma, chronic leukaemia or acute leukaemia.
 21. Amethod according to claim 1, wherein R¹ is H, —OH, —OA, phenoxy,—O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A or Hal.
 22. A method according to claim1, wherein R¹ is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂Aor Hal, R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal, R³ is H, and R¹ and R² together are alternatively methylenedioxy orethylenedioxy.
 23. A method according to claim 1, wherein R¹ is —OH,—OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A or Hal, R² is H, —OH, —OA,phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A or Hal, R³ is H, R¹ and R²together are alternatively methylenedioxy or ethylenedioxy, and Het is amonocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclicring having from 1 to 4 N, O and/or S atoms, which may be unsubstitutedor mono-, di- or trisubstituted by Hal and/or A.
 24. A method accordingto claim 1, wherein R¹ is —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A,—OSO₂A or Hal, R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A,—OSO₂A or Hal R³ is H, R¹ and R² together are alternativelymethylenedioxy or ethylenedioxy, and Het is a monocyclic or bicyclic,aromatic heterocyclic ring having from 1 to 3 N, O and/or S atoms, whichmay be unsubstituted or mono-, di- or trisubstituted by Hal and/or A.25. A method according to claim 1, wherein R¹ is —OH or —OA, R² is H,—OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A or Hal, R³ is H, R¹and R² together are alternatively methylenedioxy or ethylenedioxy, andHet is a monocyclic or bicyclic, aromatic heterocyclic ring having from1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- ortrisubstituted by Hal and/or A.
 26. A method according to claim 1,wherein R¹ is —OH or —OA, R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H,—OSO₃A, —OSO₂A or Hal, R³ is H, R¹ and R² together are alternativelymethylenedioxy or ethylenedioxy, Het is chromen-2-onyl, benzothiazolyl,thienyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl,isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl orisoquinolyl, each of which is unsubstituted or mono- or disubstituted byHal and/or A, and A is unbranched or branched alkyl having 1-6 carbonatoms, where 1-5H atoms may be replaced by F.
 27. A compound salt orsolvate of formula I

in which R¹ is —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H,—OSO₃A, —OSO₂A, SO₂A, COOH, COOA, CONH₂, NHSO₂A, COA, CHO or SO₂NH₂, R²is H, —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H, —OSO₃A,—OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO or SO₂NH₂, R³ isH, —OH, —OA, phenoxy, Ar, —O—CO-A, SO₃H, SO₃A, —OSO₃H, —OSO₃A, —OSO₂A,SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO or SO₂NH₂, R¹ and R²together are alternatively methylenedioxy or ethylenedioxy, Het is amonocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclicring having from 1 to 4 N, O and/or S atoms, which may be unsubstitutedor mono-, di- or trisubstituted by carbonyl oxygen, ═S, ═NH, Hal, A,—(CH₂)_(o)—Ar, —(CH₂)_(o)—Cycloalkyl, —(CH₂)_(o)—OH, —(CH₂)_(o)—NH₂,NO₂, CN, —(CH₂)_(o)—COOH, —(CH₂)_(o)—COOA, —(CH₂)_(o)—CONH₂,—(CH₂)_(o)—NHCOA, NHCONH₂, —(CH₂)_(o)—NHSO₂A, CHO, COA′, SO₂NH₂ and/orS(O)_(o)A, Ar is phenyl, naphthyl or biphenyl, each of which isunsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NH₂,NO₂, CN, COOH, COOA, CONH₂, NHCOA, NHCONH₂, NHSO₂A, CHO, COA, SO₂NH₂ orS(O)_(o)A, A is unbranched or branched alkyl having 1-10 carbon atoms,where 1-7H atoms may be replaced by F, A′ is alkyl having from 1 to 6carbon atoms or benzyl, Hal is F, Cl, Br or I, and o is 0, 1 or
 2. 28. Acompound, salt or solvate according to claim 27, wherein R¹ is —OH, —OA,phenoxy, —O—CO-A, —OSO₃H, —OSO₃A or —OSO₂A.
 29. A compound, salt orsolvate according to claim 28, wherein R¹ is —OH or —OA.
 30. A compound,salt or solvate according to claim 27, wherein R¹ is —OH, —OA, phenoxy,—O—CO-A, —OSO₃H, —OSO₃A or —OSO₂A, R² is H, —OH, —OA, phenoxy, —O—CO-A,—OSO₃H, —OSO₃A, —OSO₂A or Hal, R³ is H, and R¹ and R² together arealternatively methylenedioxy or ethylene dioxy.
 31. A compound, salt orsolvate according to claim 27, wherein R¹ is —OH, —OA, phenoxy, —O—CO-A,—OSO₃H, —OSO₃A or —OSO₂A, R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H,—OSO₃A, —OSO₂A or Hal, R³ is H, R¹ and R² together are alternativelymethylenedioxy or ethylenedioxy, and Het is a monocyclic or bicyclic,saturated, unsaturated or aromatic heterocyclic ring having from 1 to 4N, O and/or S atoms, which may be unsubstituted or mono-, di- ortrisubstituted by Hal and/or A.
 32. A compound, salt or solvateaccording to claim 27, wherein R¹ is —OH, —OA, phenoxy, —O—CO-A, —OSO₃H,—OSO₃A or —OSO₂A, R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A,—OSO₂A or Hal, R³ is H, R¹ and R² together are alternativelymethylenedioxy or ethylenedioxy, and Het is a monocyclic or bicyclic,aromatic heterocyclic ring having from 1 to 3 N, O and/or S atoms, whichmay be unsubstituted or mono-, di- or trisubstituted by Hal and/or A.33. A compound, salt or solvate according to claim 27, wherein R¹ is —OHor —OA, R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H, —OSO₃A, —OSO₂A orHal, R³ is H, R¹ and R² together are alternatively methylenedioxy orethylenedioxy, Het is chromen-2-onyl, benzothiazolyl, thienyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl,imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl,each of which is unsubstituted or mono- or disubstituted by Hal and/orA, and A is unbranched or branched alkyl having 1-6 carbon atoms, where1-5H atoms may be replaced by F.
 34. A compound, salt or solvateaccording to claim 27, wherein R¹ is —OH or —OA, R² is H, —OH, —OA orHal, R³ is H, R¹ and R² together are alternatively methylenedioxy orethylenedioxy, Het is benzothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl or thiazolyl, each ofwhich is unsubstituted or mono- or disubstituted by Hal and/or A, and Ais unbranched or branched alkyl having 1-6 carbon atoms, where 1-5Hatoms may be replaced by F.
 35. A compound, salt or solvate according toclaim 27, which is6-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,5,7-dihydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,7-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,6-(1-methyl-1H-imidazole-2-carbonyl)-1,3-dioxolo[4,5 g]chromen-8-one,5,7-dihydroxy-2-(pyridine-2-carbonyl)chromen-4-one, 6-hydroxy-2-(pyridine-2-carbonyl)chromen-4-one,6-hydroxy-2-(3,5-dichloropyrazine-2-carbonyl)chromen-4-one,6-hydroxy-2-(benzothiazolyl-2-carbonyl)chromen-4-one, or a salt orsolvate thereof.
 36. A pharmaceutical composition comprising a compoundaccording to claim 27 and a pharmaceutically acceptable carrier.
 37. Apharmaceutical composition according to claim 36, comprising a furtherpharmaceutically active ingredient.
 38. A kit comprising separate packsof (a) a compound, salt or solvate according to claim 27 or apharmaceutical composition comprising the same and a pharmaceuticallyacceptable carrier, and (b) a further pharmaceutically activeingredient, or pharmaceutical composition comprising the same and apharmaceutically acceptable carrier.
 39. A process for preparing acompound, salt or solvate according to claim 27, comprising a) reactinga compound of formula II

in which R¹ is —OH or —OA, R² is H, —OH, —OA, phenoxy, —O—CO-A, —OSO₃H,—OSO₃A, —OSO₂A or Hal, R³ is H, with a compound of formula III

in which A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, to give acompound of formula IV

in which A¹, R¹, R² and R³ are as defined above, b) then reacting thecompound of formula IV with a compound of formula V M-Het  V in whichHet is chromen-2-onyl, benzothiazolyl, thienyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl,triazolyl, tetrazolyl, quinolyl or iso quinolyl, each of which isunsubstituted or mono- or disubstituted by Hal and/or A, and M issodium, potassium or lithium, to give a compound of formula I, andoptionally c) a base or acid of formula I is converted into one of itssalts, or is brought together with a solvent to form a solvate.
 40. Amethod of treating a disease and/or dysfunction related to an oxidativestress condition, comprising administering to a patient in need thereofa compound, salt or solvate according to claim 27 or a pharmaceuticalcomposition comprising said compound, salt or solvate and apharmaceutically active carrier.
 41. A method according to claim 40,wherein the disease and/or dysfunction is memory loss or aneurodegenerative disease.
 42. A food supplement comprising a compound,salt or solvate according to claim 27 and a food carrier.
 43. A cosmeticcomposition comprising a compound, salt or solvate according to claim 27and a cosmetically acceptable carrier.
 44. A method of protecting thestress proteins of the skin, comprising administering to a patient inneed thereof a compound salt or solvate according to claim 27, or acosmetic composition comprising said compound, salt or solvate and acosmetically acceptable carrier, or a pharmaceutical compositioncomprising said compound, salt or solvate and a pharmaceuticallyacceptable carrier.
 45. A method according to claim 44, wherein atopical composition is applied to the skin.
 46. A method according toclaim 45, wherein the topical composition comprises said compound, saltor solvate in an amount of 0.0001 to 50% by weight, based on thecomposition.
 47. A method according to claim 1, wherein the compound offormula I is present in the form of a single isomer or a mixture ofisomers.
 48. A method according to claim 14, wherein the disease treatedis a non-hyperproliferative disease.
 49. A compound according to claim27, wherein the compound of formula I is present in the form of a singleisomer or a mixture of isomers.
 50. A method according to claim 1,wherein the compound of formula I is present in the form ofstereoisomers of said compound.
 51. A compound according to claim 27,wherein the compound of formula I is present in the form ofstereoisomers of said compound.
 52. A method according to claim 1,wherein Ar is phenyl.
 53. A compound, salt or solvate according to claim27, wherein Ar is phenyl.
 54. A method according to claim 1, wherein thecompound of formula I is6-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,5,7-dihydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,7-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,6-(1-methyl-1H-imidazole-2-carbonyl)-1,3-dioxolo[4,5 g]chromen-8-one,5,7-dihydroxy-2-(pyridine-2-carbonyl)chromen-4-one,6-hydroxy-2-(pyridine-2-carbonyl)chromen-4-one,6-hydroxy-2-(3,5-dichloropyrazine-2-carbonyl)chromen-4-one,6-hydroxy-2-(benzothiazolyl-2-carbonyl)chromen-4-one, or a salt orsolvate thereof.
 55. A method according to claim 40, wherein thecompound of formula I is6-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,5,7-dihydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,7-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,6-(1-methyl-1H-imidazole-2-carbonyl)-1,3-dioxolo[4,5 g]chromen-8-one,5,7-dihydroxy-2-(pyridine-2-carbonyl)chromen-4-one,6-hydroxy-2-(pyridine-2-carbonyl)chromen-4-one,6-hydroxy-2-(3,5-dichloropyrazine-2-carbonyl)chromen-4-one,6-hydroxy-2-(benzothiazolyl-2-carbonyl)chromen-4-one, or a salt orsolvate thereof.
 56. A method according to claim 44, wherein thecompound of formula I is6-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,5,7-dihydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,7-hydroxy-2-(1-methyl-1H-imidazole-2-carbonyl)chromen-4-one,6-(1-methyl-1H-imidazole-2-carbonyl)-1,3-dioxolo[4,5 g]chromen-8-one,5,7-dihydroxy-2-(pyrid ine-2-carbonyl)chromen-4-one, 6-hydroxy-2-(pyridine-2-carbonyl)chromen-4-one,6-hydroxy-2-(3,5-dichloropyrazine-2-carbonyl)chromen-4-one,6-hydroxy-2-(benzothiazolyl-2-carbonyl)chromen-4-one, or a salt orsolvate thereof.